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EP1015007A1 - Analogs of peptide yy and uses thereof - Google Patents

️Wed Jul 05 2000

EP1015007A1 - Analogs of peptide yy and uses thereof - Google Patents

Analogs of peptide yy and uses thereof

Info

Publication number

EP1015007A1

EP1015007A1 EP96942759A EP96942759A EP1015007A1 EP 1015007 A1 EP1015007 A1 EP 1015007A1 EP 96942759 A EP96942759 A EP 96942759A EP 96942759 A EP96942759 A EP 96942759A EP 1015007 A1 EP1015007 A1 EP 1015007A1 Authority

European Patent Office

Prior art keywords

arg

leu

seq

pyy

ala

Prior art date

1996-11-13

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Withdrawn

Application number

EP96942759A

Other languages

German (de)

French (fr)

Inventor

Ambikaipakan Balasubramaniam

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

University of Cincinnati

Original Assignee

University of Cincinnati

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1996-11-13

Filing date

1996-11-13

Publication date

2000-07-05

1996-11-13 Application filed by University of Cincinnati filed Critical University of Cincinnati

2000-07-05 Publication of EP1015007A1 publication Critical patent/EP1015007A1/en

Status Withdrawn legal-status Critical Current

Links

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235000015097 nutrients Nutrition 0.000 claims abstract description 4
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150000001875 compounds Chemical class 0.000 claims description 43
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125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
150000002334 glycols Chemical class 0.000 description 1
230000010243 gut motility Effects 0.000 description 1
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
125000001165 hydrophobic group Chemical group 0.000 description 1
230000002706 hydrostatic effect Effects 0.000 description 1
125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
238000007455 ileostomy Methods 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
210000000936 intestine Anatomy 0.000 description 1
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238000007912 intraperitoneal administration Methods 0.000 description 1
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229910052740 iodine Inorganic materials 0.000 description 1
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AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
229960000310 isoleucine Drugs 0.000 description 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
239000008101 lactose Substances 0.000 description 1
125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
229910001629 magnesium chloride Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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238000005259 measurement Methods 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
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239000002480 mineral oil Substances 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
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108010058785 neuropeptide Y (13-36) Proteins 0.000 description 1
BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
239000002858 neurotransmitter agent Substances 0.000 description 1
FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
231100000344 non-irritating Toxicity 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
235000021231 nutrient uptake Nutrition 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
229960003104 ornithine Drugs 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
238000004806 packaging method and process Methods 0.000 description 1
210000000496 pancreas Anatomy 0.000 description 1
230000036961 partial effect Effects 0.000 description 1
239000002245 particle Substances 0.000 description 1
239000000312 peanut oil Substances 0.000 description 1
108010071588 peptide YY (13-36) Proteins 0.000 description 1
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229940124531 pharmaceutical excipient Drugs 0.000 description 1
239000012071 phase Substances 0.000 description 1
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
230000001766 physiological effect Effects 0.000 description 1
239000004926 polymethyl methacrylate Substances 0.000 description 1
239000011148 porous material Substances 0.000 description 1
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230000002265 prevention Effects 0.000 description 1
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238000011321 prophylaxis Methods 0.000 description 1
SSJGXNSABQPEKM-SBUIBGKBSA-N pyy peptide Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 SSJGXNSABQPEKM-SBUIBGKBSA-N 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
238000009877 rendering Methods 0.000 description 1
238000004366 reverse phase liquid chromatography Methods 0.000 description 1
235000009566 rice Nutrition 0.000 description 1
238000004626 scanning electron microscopy Methods 0.000 description 1
230000007017 scission Effects 0.000 description 1
230000000580 secretagogue effect Effects 0.000 description 1
UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
239000008159 sesame oil Substances 0.000 description 1
235000011803 sesame oil Nutrition 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
235000020183 skimmed milk Nutrition 0.000 description 1
210000000813 small intestine Anatomy 0.000 description 1
210000002460 smooth muscle Anatomy 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
239000007790 solid phase Substances 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000002731 stomach secretion inhibitor Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
208000011580 syndromic disease Diseases 0.000 description 1
235000015523 tannic acid Nutrition 0.000 description 1
LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
229940033123 tannic acid Drugs 0.000 description 1
229920002258 tannic acid Polymers 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
108010080629 tryptophan-leucine Proteins 0.000 description 1
108010020532 tyrosyl-proline Proteins 0.000 description 1
108010003137 tyrosyltyrosine Proteins 0.000 description 1
238000012762 unpaired Student’s t-test Methods 0.000 description 1
239000004474 valine Substances 0.000 description 1
125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
230000025033 vasoconstriction Effects 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
238000005406 washing Methods 0.000 description 1
238000009736 wetting Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

This invention relates to peptide derivatives which are useful as therapeutic agents in the treatment of gastroenterological disorders.
Peptide YY is a 36-residue peptide amide isolated originally from porcine intestine, and localized in the endocrine cells of the gastrointestinal tract and pancreas (Tatemoto et al. Proc . Natl . Acad . Sci . 79:2514, 1982) .
Peptide YY has N-terminal and C-terminal tyrosine amides; accordingly, these two tyrosines give PYY its name (Y represents the amino acid tyrosine in the peptide nomenclature) .
PYY has a number of central and peripheral regulatory roles with its homologous peptide neuropeptide Y (NPY) , which was originally isolated from porcine brain (Tatemoto, Proc . Natl . Acad . Sci . 79:5485, 1982). In contrast with the cellular location of PYY, NPY is present in submucous and myenteric neurons which innervate the mucosal and smooth muscle layers, respectively (Ekblad et al. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibit gut motility and blood flow (Laburthe, Trends Endocrinol . Metab .
PYY receptor system which exhibits a slightly higher affinity for PYY than NPY has been characterized in rat intestinal epithelia (Laburthe et al. Endocrinology 118:1910, 1986; Laburthe, Trends Endocrinol . Metab . supra) and shown to be negatively coupled to adenylate cyclase (Servin et al. Endocrinology 124:692, 1989). Consistently, PYY exhibited greater antisecretory potency than NPY in voltage clamped preparations of rat small intestine (Cox et al. J . Physiol . supra) , while
PYY has been implicated in a number of physiological activities including nutrient uptake (see, e.g., Bilcheik et al. Digestive Disease Week
porcine and human PYY are as follows : porcine PYY YPAKPEAPGEDASPEELSRYYAS RHYLNLVTRQRY ( SEQ . ID . NO .
the amino acid sequence for dog PYY and rat is the same as porcine PYY.
the present invention features novel analogs of peptide YY of the formula:
X is a chain of 0-5 amino acids, inclusive, the N- terminal one of which is bonded to R 2 and R 2 ;
Y is a chain of 0-4 amino acids, inclusive, the C- terminal one of which is bonded to R 3 and R 4 ;
R- L is H, C- L -C- L2 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristoyl) ,
C 7 -C 18 aralkyl e.g., benzyl
C 7 -C 18 alkaryl e.g., p-methylphenyl
R 2 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristoyl),
C 7 -C 18 aralkyl e.g. , benzyl
C 7 -C 18 alkary1 e.g., p-methylpheny1
a 22 is an aromatic amino acid, Ala, Aib, Anb, N- Me- Ala, or is deleted
a 23 is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N Me- Ala, or is deleted;
a 24 is Leu, lie, Val, Trp, Gly, Nle, Nva, Aib, Anb, N-Me-Leu, or is deleted;
a 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C_-C 10 alkyl group, or an aryl group) , Orn, or is deleted;
a 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, ⁇ - pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or an aryl group) , Orn, or is deleted;
a 27 is an aromatic amino acid other than Tyr;
a 28 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or
a 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn;
a 30 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;
a 31 is Val, Leu, lie, Trp, Nle, Nva, Aib, Anb, or
N-Me-Val; A 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp;
R 3 is H, C--C-, ⁇ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl), C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl) ; and R 4 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl), C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristo
X is A 17 -A 18 -A 19 -A 20 -A 21 wherein A 17 is Cys, Leu, lie, Val, Nle, Nva, Aib, Anb, or N-Me-Leu; A 18 is Cys, Ser, Thr, N-Me-Ser, or N-Me-Thr; A 19 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ C ⁇ alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; A 20 is an aromatic amino acid, or Cys; and A 21 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. In yet other preferred embodiments, Y is A 33 -
a 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ C- ⁇ alkyl group, or an aryl group) , Cys, or Orn;
a 34 is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Aib, or
Anb; A 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ C- ⁇ alkyl group, or an aryl group) ,
the compound has the formula: N- ⁇ -Ac- Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg- Tyr-NH 2 (SEQ. ID. NO. 3), H-Ala-Ser-Leu-Arg-His-Phe-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO.
N- ⁇ -Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln- Arg-Tyr-NH 2 SEQ. ID. NO. 5
N- ⁇ -Ac-Ala-Ser-Leu-Arg-His- Thi-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 SEQ. ID. NO. 6)
N- ⁇ -Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH 2 SEQ. ID. NO. 7) or a pharmaceutically acceptable salt thereof.
the invention features novel analogs of peptide YY of the formula: R ⁇ R 3
N-terminal amino acid is bonded to R ⁇ and R 2 ;
Y is a chain of 0-4 amino acids, inclusive the C- terminal one of which is bonded to R 3 and R 4 ;
R ⁇ is H, C -C- L2 alkyl (e.g., methyl), C 6 -C 18 aryl
R 2 is H, C- L -C- L2 alkyl (e.g., methyl), C 6 -C 18 aryl
a 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ -C ⁇ alkyl group, or an aryl group) ,
a 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, ⁇ - pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C ⁇ C- ⁇ alkyl group, or an aryl group) , Orn, or is deleted;
a 27 is an aromatic amino acid;
a 28 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;
a 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn;
a 30 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or
a 31 is Val, lie, Trp, Nva, Aib, Anb, or N-Me-Val;
a 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp;
R 3 is H, C- L -C- ⁇ alkyl (e.g., methyl), C 6 -C 18 aryl
phenyl e.g., phenyl, napthaleneacetyl
C ⁇ C- ⁇ acyl e.g., formyl, acetyl, and myristoyl
C 7 -C 18 aralkyl e.g., benzyl
C 7 -C 18 alkaryl e.g., p-methylphenyl
R 4 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl
a 27 is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip.
Y is A 33 -A 34 -A 35 -A 36 wherein
a 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn;
a 34 is Gin, Asn, Ala, Gly, N-Me-Gln, Aib, Cys, or
a 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; and
a 36 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof.
the compound has the formula N- ⁇ -Ac- Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 8) .
the invention features novel dimeric analogs of peptide YY.
the dimer may be formed by either including two peptides of Formula I, two peptides of Formula II, or one peptide of Formula I and one peptide of Formula II.
the dimer is formed by utilizing a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each peptide.
a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each peptide.
suitable dicarboxylic acid linkers are succinic acid, gluta ic acid, and phthalic acid.
the dimer is formed by utilizing an amino acid linker capable of binding to a free amine group of one peptide and a free carboxyl group of the other peptide.
the amino acid linker is a non ⁇ -amino acid.
Suitable amino acid linkers are amino-caproic acid and amino-valeric acid.
the dimer is formed by a disulfide bridge between cysteines located within each peptide. See, e.g., M. Berngtowicz and G. Piatsueda,
the invention features analogs of Formula I or Formula II having at least one pseudopeptide bond between amino acid residues.
pseudopeptide bond is meant that the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon, i.e., CH 2 - NH; or less preferably that of CO-NH is replaced with any of CH 2 -S, CH 2 -CH 2 , CH 2 -0, or CH 2 -CO.
a pseudopeptide peptide bond is symbolized herein by “ ⁇ " .
the pseudopeptide bonds are located between one or more amino acid residues, e.g., A 28 ⁇ A 29 , A 29 ⁇ A 30 , A 30 ⁇ A 31 , A 31 ⁇ A 32 , A 32 ⁇ A 33 , A 33 ⁇ A 34 , A 34 ⁇ A 35 , or A 35 ⁇ A 36 .
such pseudopeptide bond analogs can be used to form dimeric analogs as is described above. A detailed discussion of the chemistry of pseudopeptide bonds is given in Coy et al. (1988) Tetrahedron 44:835-841.
the invention features radiolabeled analogs of Formula I and Formula II.
the analogs have a tyrosine iodinated on the phenyl ring at carbon position 3 or 5.
the radioactive iodine is preferably I 125 or I 123 .
R is -CH 2 COOH for Asp
R is -H for Gly
R is - CH 2 0H for Ser
R is -CH 3 for Ala
R is -CH 2 CH 2 CH 2 CH 2 NH 2 for Arg.
amino acid residue when optically active, it is the L-form configuration that is intended unless the D-form is expressly designated.
Tic tetrahydroisoquinoline-3-carboxylic acid
Aib aminoisobutyric acid
the compounds of the present invention can be provided in the form of pharmaceutically acceptable salts.
preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, trifluoroacetic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids, such as hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid and the like.
the invention features one of the above compounds and a pharmaceutically acceptable carrier substance in a therapeutic composition capable of decreasing excess intestinal water and electrolyte secretion.
the composition is in the form of a liquid, pill, tablet, or capsule for oral administration; a liquid capable of being administered nasally as drops or spray or a liquid for intravenous, subcutaneous, parenteral, intraperitoneal or rectal administration.
the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration. For maximum efficacy, zero-order release is desired.
the invention features, a method for decreasing excess intestinal water and electrolyte secretion in a mammal, the method comprising administering to the mammal, e.g., a human, a therapeutically effective amount of the above mentioned compounds .
the invention features a method of regulating cell proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the composition of the above mentioned compounds.
the method regulates the proliferation of an intestinal cell.
the invention also features methods for increasing nutrient transport, regulating lipolysis, and regulating blood flow in a mammal, the methods comprising administering to the mammal a therapeutically effective amount of the above mentioned compositions.
the compounds of the invention exhibit a broad range of biological activities related to their antisecretory and antimotility properties.
the compounds are believed to suppress gastrointestinal secretions by direct interaction with epithelial cells or, perhaps, by inhibiting secretion of hormones or neurotransmitters which stimulate intestinal secretion.
the compounds of the invention may also control intestinal blood flow which in turn may modulate intestinal hydrostatic pressure in favor of net water absorption.
the compounds of the invention are especially useful in the treatment of any number of gastrointestinal disorders (see e.g., Harrison 's Principles of Internal Medicine , McGraw-Hill Inc., New York, 12th Ed.) that are associated with excess intestinal electrolyte and water secretion as well as decreased absorption, e.g., infectious (e.g., viral or bacterial) diarrhea, inflammatory diarrhea, short bowel syndrome, or the diarrhea which typically occurs following surgical procedures, e.g., ileostomy.
infectious diarrhea examples include, without limitation, acute viral diarrhea, acute bacterial diarrhea (e.g., salmonella, campylobacter , and clostridium or due to protozoal infections), or traveller's diarrhea (e.g., Norwalk virus or rotavirus) .
infectious diarrhea examples include, without limitation, malabsorption syndrome, tropical spue, chronic pancreatitis, Crohn's disease, diarrhea, and irritable bowel syndrome.
the peptides of the invention can be used to treat an emergency or life-threatening situation involving a gastrointestinal disorder, e.g., after surgery or due to cholera.
the compounds of the invention can be used to treat patients suffering from Acquired Immune Deficiency Syndrome (AIDS) , especially during cachexia.
AIDS Acquired Immune Deficiency Syndrome
the compounds of the invention are also useful for inhibiting small intestinal fluid and electrolyte secretion, augmenting nutrient transport — as well as increasing cell proliferation — in the gastrointestinal tract, regulating lipolysis in, e.g, adipose tissue, and regulating blood flow in a mammal.
the compounds of the invention are advantageous because they are truncated versions of the natural PYY peptide; thus, the shorter peptide not only facilitates easier synthesis and purification of the compounds, but also improves and reduces manufacturing procedures and expenses.
FIG. 1 shows a semipreparative reversed phase chromatogram of N- ⁇ -Ac- [Phe 27 ] PYY (22-36) (SEQ. ID. NO. 3) ( «25mg) obtained by HF cleavage.
FIG. 2 shows a graph of the inhibition of 125 i- PYY binding to rat jejunal membranes by increasing concentrations of PYY (SEQ. ID. NO. 1), PYY (22-36) (SEQ. ID. NO. 10), [Im-DNP-His 26 ]PYY (SEQ. ID. NO. 9),
FIGS. 3A-B show the antisecretory effects of PYY (SEQ. ID. NO. 1), PYY(22-36) (SEQ. ID. NO. 10) and analogs up one baseline short circuit current (SCC) in voltage clamped preparation of rat jejunum. Values of changes in SCC are quoted of ⁇ A/0.6cm 2 , mean ⁇ SEM from between 3 and 7 different jejunal preparations. Peptides shown in A and B are denoted by the same symbol as in FIG. 2.
FIG. 4 shows a graph of the inhibition of 125 I-PYY binding to rat jejunal membranes by increasing concentrations of PYY, N- ⁇ -Ac-PYY (22-36) (SEQ. ID. NO. 14), N- ⁇ -Ac-[Tic 27 ]PYY(22-36) (SEQ. ID. NO. 25), N- ⁇ -Ac- [Bip 27 ]PYY(22-36) (SEQ. ID. NO. 22), N- ⁇ -Ac- [Nal 27 ]PYY (22- 36) (SEQ. ID. NO. 23), N- ⁇ -Ac- [Bth 27 ]PYY (22-36) (SEQ. ID. NO.
N- ⁇ -Ac- [Phe 27 ] PYY (22-36) (SEQ. ID. NO. 3), N- ⁇ -Ac- [Phe 27 ]PYY(25-36) (SEQ. ID. NO. 26), N- ⁇ -Ac- [Trp 27 ] PYY (22- 36) (SEQ. ID. NO. 5), and N- ⁇ -Ac- [Thi 27 ]PYY (22-36) (SEQ. ID. NO. 6) .
the peptides of the invention have the general formula recited in the Summary of the Invention above. They all have an aromatic amino acid group at position 27 which is important for both antisecretory activity and utility as antidiarrheal compounds.
the peptides of the present invention may be synthesized by any techniques that are known to those skilled in the peptide art. An excellent summary of the many techniques so available may be found in Solid Phase Peptide Synthesis 2nd ed. (Stewart, J.M. and Young, J. D. Pierce Chemical Company, Rockford, IL, 1984) .
peptides listed in Table 1 and Table 2 were synthesized as follows. Peptide synthesis was performed on an Applied Biosystems Model 430A synthesizer. Amino acid and sequence analyses were carried out using Waters Pico-Tag and Applied Biosystems Model 470A instruments, respectively. Peptides were purified using a Waters Model 600 solvent delivery system equipped with a Model 481 Spectrophotometer and U6K injector according to standard protocols. Peptide masses were determined at the University of Michigan, Protein Chemistry Facility, Ann Arbor, Michigan according to standard methods. All Boc-L-amino acid derivatives, solvents, chemicals and the resins were obtained commercially and used without further purification.
Paramethylbenzhydroxyla ine (MBHA) resin (0.45 mmol, -NH 2 ) was placed in the reaction vessel of the peptide synthesizer and the protected amino acid derivatives were sequentially coupled using the program provided by the manufacturers modified to incorporate a double coupling procedure (see, e.g., Balasubramaniam et al., Peptide Research 1: 32, 1988). All amino acids were coupled using 2.2 equivalents of preformed symmetrical anhydrides. Arg, Gin and Asn, however, were coupled as preformed 1-hydroxybenzotriazole (HOBT) esters to avoid side reactions.
HOBT 1-hydroxybenzotriazole
the N- ⁇ -Boc group was removed and in some instances the free ⁇ -NH2 was acetylated by reaction with acetic anhydride (2 equivalents) and diisopropyl ethylamine until a negative ninhydrin test was obtained (Anal. Biochem. 34:595, 1970).
the peptide resin (-1.0 g) was then treated with HF (10 ml) containing p-cresol (-0.8 g) for 1 h at -2 to -4 °C.
Binding experiments were conducted in a total volume of 0.25 ml 60 mM HEPES buffer, pH 7, containing 2% BSA, 0.1% bacitracin, 5 mM MgCl 2 and 0.05 nM 125 ⁇ -p ⁇ with or without competing peptides. Bound and free peptides were separated by centrifugation at 20,000 X g for 10 min.
Non-specific 125 I-PYY binding was determined in the presence of 1 ⁇ M unlabeled PYY represented 10% of the total binding.
SCC short-circuit current
Preparations were automatically voltage clamped using a W-P dual voltage clamp and the SCC displayed continuously on pen recorders. Once a stable baseline SCC was reached, peptides were added to the basolateral reservoir only, and cumulative concentration-response profiles constructed. Data Analyses All points in the binding experiments are the mean of at least three experiments performed in duplicate.
Fig. 1 shows the RP-HPLC chromatogram of N- ⁇ -Ac- [Phe 27 ] PYY (22-36) (SEQ. ID. NO. 3).
the free peptides were further characterized by sequence analysis (see, Table 1 and Table 2) .
the overall yields of the peptides were in the range of 10% to 30%.
PEPTIDES RT d MH+ (Calc.) BINDING 1 " SCC L (min) IC 50 (nM) EC 5Q (nM)
a isocratic, 27% CH,CN containing 0.1% TFA
b mean of three separate experiments
c isocratic, 32% CH--CN containing 0.1% TFA
d from reference 10; n.d.: not determined
N- ⁇ -myristoyl-PYY (22-36) (SEQ. ID. NO. 18) and N- ⁇ - naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19) analogs in contrast to their moderate binding potency, exhibited poor antisecretory responses with threshold 5 concentrations of about 20nM and EC 50 values greater than 2 and 30 ⁇ M respectively.
Subsequent addition of PYY (100 nM) further l ⁇ reduced the SCC by
N- ⁇ -myristoyl-PYY (22-36) SEQ. ID. NO. 18
N- ⁇ - naphthaleneacetyl-PYY (22-36) SEQ. ID. NO. 19
analogs inhibited 125 I-PYY binding with moderate potency, but exhibited poor antisecretory responses. This observation suggested that these analogs may be antagonists.
Table 2 and Fig. 4 present the IC 50 values for additonal PYY(22-36) (SEQ. ID. NO. 10) and PYY (25-36) analogs. Based on the results presented in Table 2 the analogs in this series exhibited the following order of potency: N- ⁇ -Ac-[Tic 27 ]PYY(22-36) (SEQ. ID. NO. 25) ⁇ N- ⁇ -Ac- [Bip 27 ]PYY(22-36) (SEQ. ID. NO.
NPY/PYY receptors characterized to date have been broadly classified into Y-l, Y-2 and Y-3 subtypes (Balsubramaniam et al. J . Biol . Chem . 265:14724, 1990; Michel, Trends Pharmacol . Sci . 12:389, 1991). Both Y-l and Y-2 receptors exhibit a preference for PYY over NPY, and more significantly C-terminal fragments of NPY and PYY are effective only at the Y-2 subtype. Y-3 receptors, on the other hand, exhibit a greater affinity for NPY than PYY. Since rat jejunal mucosa antisecretory responses show an order of agonist potency PYY (SEQ. ID.
an effective amount of an any one or combination of the analogs of the invention e.g. , N- ⁇ - Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3), N- ⁇ -Ac-
compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously) , rectally ( e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or either solid, liquid or gaseous dosage, including tablets and suspensions.
the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
the method of the present invention is practiced when relief of symptoms is specifically required or perhaps imminent.
the method of the present invention is effectively practiced as continuous or prophylactic treatment.
Useful pharmaceutical carriers for the preparation of the compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid- protein vesicles) , sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like.
the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like.
formulation for intravenous administration comprise sterile aqueous solutions of the active ingredient (s) which are prepared by dissolving solid active ingredient (s) in water to produce an aqueous solution, and rendering the solution sterile.
Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
Suitable pharmaceutical carriers and their formulation are described in Remington 's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
the dose of the compound of the present invention for treating the above-mentioned disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian.
Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount".
a typical administration is oral administration or parenteral administration.
the daily dose in the case of oral administration is typically in the range of 0.1 to 100 mg/kg body weight, and the daily dose in the case of parenteral administration is typically in the range of 0.001 to 50 mg/kg body weight.
the therapeutic agents be relatively non-toxic, non-antigenic and non-irritating at the levels in actual use.
Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu
Xaa in position 15 is an abbreviation of N-Me-Tyr.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 6 is an abbreviation of Thi (2-thienylalanine) .
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-) .
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 26 is an abbreviation of im-DNP-His.
the sequence has an acetylated N- terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N- ).
the sequence has an amide C-terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 5 is an abbreviation of p.Cl.Pro.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 15 is an abbreviation of N-Me-Tyr.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH).
the sequence has a myristoylated N-terminus (i.e., N- ⁇ -myristoyl) , rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
the sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., C0- OH) .
Xaa in position 6 is an abbreviation of Bth.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide c-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 6 is an abbreviation of Bip.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 6 is an abbreviation of Nal.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 6 is an abbreviation of Tic.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 15 is an abbreviation of Thi.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
Xaa in position 15 is an abbreviation of Thz.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH).
Xaa in position 6 is an abbreviation of Pep.
the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

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Abstract

The invention provides analogs of PYY. The invention also provides compositions and methods useful for controlling biological activities such as cell proliferation, nutrient transport, lipolysis, and intestinal water and electrolyte secretion.

Description

ANALOGS OF PEPTIDE YY AND USES THEREOF Statement as To Federally Sponsored Research This invention was made in part with Government funding and the Government therefore has certain rights in the invention.

Background of the Invention This invention relates to peptide derivatives which are useful as therapeutic agents in the treatment of gastroenterological disorders.

Peptide YY (PYY) is a 36-residue peptide amide isolated originally from porcine intestine, and localized in the endocrine cells of the gastrointestinal tract and pancreas (Tatemoto et al. Proc . Natl . Acad . Sci . 79:2514, 1982) . Peptide YY has N-terminal and C-terminal tyrosine amides; accordingly, these two tyrosines give PYY its name (Y represents the amino acid tyrosine in the peptide nomenclature) . In addition PYY shares a number of central and peripheral regulatory roles with its homologous peptide neuropeptide Y (NPY) , which was originally isolated from porcine brain (Tatemoto, Proc . Natl . Acad . Sci . 79:5485, 1982). In contrast with the cellular location of PYY, NPY is present in submucous and myenteric neurons which innervate the mucosal and smooth muscle layers, respectively (Ekblad et al. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibit gut motility and blood flow (Laburthe, Trends Endocrinol . Metab . 1:168, 1990), and they are also thought to attenuate basal (Cox et al. Br. J . Pharmacol . 101:247, 1990; Cox et al. J . Physiol . 398:65, 1988; Cox et al. Peptides 12:323, 1991; Friel et al. Br. J. Pharmacol . 88:425, 1986) and secretagogue-induced intestinal secretion in rats (Lundberg et al. Proc . Natl . Acad . Sci USA 79:4471, 1982; Playford et al. Lancet 335:1555, 1990) and humans (Playford et al. supra) , as well as stimulate net absorption (MacFadyen et al. Neuropeptides 7:219, 1986) . Furthermore, plasma PYY levels have been reported to be elevated in several diseases that cause diarrhea (Adrian et al. Gastroenterology 89:1070, 1985). Taken together, these observations suggest that PYY and NPY are released into the circulation after a meal (Adrian et al. Gastroenterology 89:1070, 1985; Balasubramaniam et al. Neuropeptides 14:209, 1989), and thus may play a physiological role in regulating intestinal secretion and absorption, serving as natural inhibitors of diarrhea.

A high affinity PYY receptor system which exhibits a slightly higher affinity for PYY than NPY has been characterized in rat intestinal epithelia (Laburthe et al. Endocrinology 118:1910, 1986; Laburthe, Trends Endocrinol . Metab . supra) and shown to be negatively coupled to adenylate cyclase (Servin et al. Endocrinology 124:692, 1989). Consistently, PYY exhibited greater antisecretory potency than NPY in voltage clamped preparations of rat small intestine (Cox et al. J . Physiol . supra) , while

C-terminal fragments of NPY were found to be less effective in their antisecretory potency than PYY (Cox et al. Br. J. Pharmacol , supra) . Structure-activity studies using several partial sequences have led to the identification of PYY (22-36) as the active site for interacting with intestinal PYY receptors (Balsubramaniam et al. Pept . Res . 1:32, 1988).

In addition, PYY has been implicated in a number of physiological activities including nutrient uptake (see, e.g., Bilcheik et al. Digestive Disease Week

506:623, 1993), cell proliferation (see, e.g., Laburthe, Trends Endocrinol . Metab . 1:168, 1990; Voisin et al. J . Biol . Chem, 1993), lipolysis (see, e.g., Valet et al. , J . Clin . Invest . 85:291, 1990), and vasoconstriction ( see , e . g . , Lundberg et al . , Proc . Natl . Acad . SCi . , USA 79 : 4471 , 1982 ) .

The amino acid sequences of porcine and human PYY are as follows : porcine PYY YPAKPEAPGEDASPEELSRYYAS RHYLNLVTRQRY ( SEQ . ID . NO .

1) human PYY YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ . ID . NO .

2 )

The amino acid sequence for dog PYY and rat is the same as porcine PYY.

Summary of the Invention In one aspect, the present invention features novel analogs of peptide YY of the formula:

^Rι ^R3

R₂-X-A²²-A²³-A² -A²⁵-A²⁵-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-Y-R₄

(Formula I)

wherein

X is a chain of 0-5 amino acids, inclusive, the N- terminal one of which is bonded to R₂ and R₂;

Y is a chain of 0-4 amino acids, inclusive, the C- terminal one of which is bonded to R₃ and R₄;

R-_L is H, C-_L-C-_L2 alkyl (e.g., methyl), C₆-C₁₈ aryl (e.g., phenyl, naphthaleneacetyl) , C^C-^ acyl (e.g., formyl, acetyl, and myristoyl) ,

C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g., p-methylphenyl) ; R₂ is H, C₁-C₁₂ alkyl (e.g., methyl), C₆-C₁₈ aryl (e.g., phenyl, naphthaleneacetyl) , C^C-^ acyl (e.g., formyl, acetyl, and myristoyl),

C₇-C₁₈ aralkyl (e.g. , benzyl) , or C₇-C₁₈ alkary1 (e.g., p-methylpheny1) ; A²² is an aromatic amino acid, Ala, Aib, Anb, N- Me- Ala, or is deleted; A²³ is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N Me- Ala, or is deleted;

A²⁴ is Leu, lie, Val, Trp, Gly, Nle, Nva, Aib, Anb, N-Me-Leu, or is deleted;

A²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C_-C₁₀ alkyl group, or an aryl group) , Orn, or is deleted; A²⁶ is Ala, His, Thr, 3-Me-His, 1-Me-His, β- pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C₁-C₁₀ alkyl group, or an aryl group) , Orn, or is deleted; A²⁷ is an aromatic amino acid other than Tyr;

A²⁸ is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or

N-Me-Leu; A²⁹ is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A³⁰ is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;

A³¹ is Val, Leu, lie, Trp, Nle, Nva, Aib, Anb, or

N-Me-Val; A³² is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R₃ is H, C--C-,^ alkyl (e.g., methyl), C₆-C₁₈ aryl (e.g., phenyl, naphthaleneacetyl), C^C-^ acyl (e.g., formyl, acetyl, and myristoyl), C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g., p-methylphenyl) ; and R₄ is H, C₁-C₁₂ alkyl (e.g., methyl), C₆-C₁₈ aryl (e.g., phenyl, naphthaleneacetyl), C^C-^ acyl (e.g., formyl, acetyl, and myristoyl), C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g., p-methylphenyl), or a pharmaceutically acceptable salt thereof. In preferred embodiments, A²⁷ is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip.

In preferred embodiments X is A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹ wherein A¹⁷ is Cys, Leu, lie, Val, Nle, Nva, Aib, Anb, or N-Me-Leu; A¹⁸ is Cys, Ser, Thr, N-Me-Ser, or N-Me-Thr; A¹⁹ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C^C^ alkyl group, or C₆-C₁₈ aryl group) , Cys, or Orn; A²⁰ is an aromatic amino acid, or Cys; and A²¹ is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. In yet other preferred embodiments, Y is A³³-

_A34__A35__A36 _wnerei_n

A³³ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) , Cys, or Orn;

A³⁴ is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Aib, or

Anb; A³⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) ,

Cys, or Orn; and A³⁶ is an aromatic amino acid, Cys or a pharmaceutically acceptable salt thereof. Preferably, the compound has the formula: N-α-Ac- Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg- Tyr-NH₂ (SEQ. ID. NO. 3), H-Ala-Ser-Leu-Arg-His-Phe-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 4) , N- α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln- Arg-Tyr-NH₂ (SEQ. ID. NO. 5) , N-α-Ac-Ala-Ser-Leu-Arg-His- Thi-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 6) , N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 7) or a pharmaceutically acceptable salt thereof.

In another aspect the invention features novel analogs of peptide YY of the formula: R_λ R₃

\ /

R₂-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-Y-R₄ (Formula II)

wherein the N-terminal amino acid is bonded to R_χ and R₂ ; Y is a chain of 0-4 amino acids, inclusive the C- terminal one of which is bonded to R₃ and R₄; R_λ is H, C -C-_L2 alkyl (e.g., methyl), C₆-C₁₈ aryl

(e.g., phenyl, napthaleneacetyl) , Cι~C₁₂ acyl (e.g., formyl, acetyl, and myristoyl), C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g. , p-methylphenyl) ; R₂ is H, C-_L-C-_L2 alkyl (e.g., methyl), C₆-C₁₈ aryl

(e.g., phenyl, napthaleneacetyl), ^-C^ acyl (e.g., formyl, acetyl, and myristoyl), C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g. , p-methylphenyl) ; A²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C^-C^ alkyl group, or an aryl group) ,

Orn, or is deleted; A²⁶ is Ala, His, Thr, 3-Me-His, 1-Me-His, β- pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) , Orn, or is deleted; A²⁷ is an aromatic amino acid;

A²⁸ is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu; A²⁹ is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn;

A³⁰ is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or

N-Me-Leu; A³¹ is Val, lie, Trp, Nva, Aib, Anb, or N-Me-Val; A³² is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp;

R₃ is H, C-_L-C-^ alkyl (e.g., methyl), C₆-C₁₈ aryl

(e.g., phenyl, napthaleneacetyl), C^C-^ acyl (e.g., formyl, acetyl, and myristoyl), C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g., p-methylphenyl); and

R₄ is H, C₁-C₁₂ alkyl (e.g., methyl), C₆-C₁₈ aryl

(e.g., phenyl, napthaleneacetyl), C^C-^ acyl (e.g., formyl, acetyl, and myristoyl), C₇-C₁₈ aralkyl (e.g., benzyl), or C₇-C₁₈ alkaryl (e.g., p-methylphenyl), or a pharmaceutically acceptable salt thereof. In preferred embodiments A²⁷ is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip.

In preferred embodiments Y is A³³-A³⁴-A³⁵-A³⁶ wherein

A³³ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C₁-C₁₀ alkyl group, or C₆-C₁₈ aryl group) , Cys, or Orn; A³⁴ is Gin, Asn, Ala, Gly, N-Me-Gln, Aib, Cys, or

Anb; A³⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain alkyl group, or C₆-C₁₈ aryl group) , Cys, or Orn; and

A³⁶ is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. Preferably, the compound has the formula N-α-Ac- Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 8) . In another aspect, the invention features novel dimeric analogs of peptide YY. The dimer may be formed by either including two peptides of Formula I, two peptides of Formula II, or one peptide of Formula I and one peptide of Formula II. In one embodiment, the dimer is formed by utilizing a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each peptide. See, e.g., R. Vavrek and J. Stewart, Peptides: Structure and Function 381-384 (Pierce Chemical Co. 1983) . Examples of suitable dicarboxylic acid linkers are succinic acid, gluta ic acid, and phthalic acid. In other embodiments, the dimer is formed by utilizing an amino acid linker capable of binding to a free amine group of one peptide and a free carboxyl group of the other peptide. Preferably, the amino acid linker is a non α-amino acid. Examples of suitable amino acid linkers are amino-caproic acid and amino-valeric acid. In yet another embodiment, the dimer is formed by a disulfide bridge between cysteines located within each peptide. See, e.g., M. Berngtowicz and G. Piatsueda,

Peptides: Structure and Function 233-244 (Pierce Chemical Co. 1985); F. Albericio, et al. , Peptides 1990. 535 (ESCOM 1991) .

In yet another aspect, the invention features analogs of Formula I or Formula II having at least one pseudopeptide bond between amino acid residues. By "pseudopeptide bond" is meant that the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon, i.e., CH₂- NH; or less preferably that of CO-NH is replaced with any of CH₂-S, CH₂-CH₂, CH₂-0, or CH₂-CO. A pseudopeptide peptide bond is symbolized herein by "ψ" . Preferably, the pseudopeptide bonds are located between one or more amino acid residues, e.g., A²⁸ΨA²⁹, A²⁹ΨA³⁰, A³⁰ΨA³¹, A³¹ΨA³², A³²ΨA³³, A³³ΨA³⁴, A³⁴ΨA³⁵, or A³⁵ΨA³⁶. In addition, such pseudopeptide bond analogs can be used to form dimeric analogs as is described above. A detailed discussion of the chemistry of pseudopeptide bonds is given in Coy et al. (1988) Tetrahedron 44:835-841. In yet another aspect, the invention features radiolabeled analogs of Formula I and Formula II. Preferably, the analogs have a tyrosine iodinated on the phenyl ring at carbon position 3 or 5. The radioactive iodine is preferably I¹²⁵ or I¹²³. An example of the chemistry associated with iodinated tyrosine residues within peptides, see European Patent Application 0389180, herein incorporated by reference. Accordingly, radiolabeled PYY analogs can be used for imaging PYY receptors, e.g., for imaging cells containing PYY receptors.

The symbol X, Y, Z, A²², A²³, A²⁴, and the like; and Ser, Leu or the like, as found in a peptide sequence herein stands for an amino acid residue, i.e., =N-CH(R)- CO- when it is at the N-terminus, or -NH-CH(R) -CO-N= when it is at C-terminus, or -NH-CH(R) -CO- when it is not at the N- or C-terminus, where R denotes the side chain (or identifying group) of an amino acid or its residue. For example, R is -CH₂COOH for Asp, R is -H for Gly, R is - CH₂0H for Ser, R is -CH₃ for Ala and R is -CH₂CH₂CH₂CH₂NH₂ for Arg. Also, when the amino acid residue is optically active, it is the L-form configuration that is intended unless the D-form is expressly designated.

As set forth above and for convenience in describing this invention, the conventional and nonconventional abbreviations for the various amino acids are used. They are familiar to those skilled in the art; but for clarity are listed below. All peptide sequences mentioned herein are written according to the usual convention whereby the N-terminal amino acid is on the left and the C-terminal amino acid is on the right. A short line between two amino acid residues indicates a peptide bond.

Asp = D = Aspartic Acid

Ala = A = Alanine

Arg = R = Arginine

Asn - N = Asparagine

Cys = C = Cysteine

Gly = G = Glycine

Glu = E = Glutamic Acid

Gin = Q = Glutamine

His = H = Histidine lie = I = Isoleucine

Leu = L = Leucine

Lys = K = Lysine

Met = M = Methionine

Phe = F = Phenylalanine

Pro = P = Proline

Ser = S = Serine

Thr = T = Threonine

Trp = = Tryptophan

Tyr = Y = Tyrosine

Val = V = Valine

Orn = Ornithine

Nal = 2-napthylalanine Nva = Norvaline

Nle = Norleucine

Thi = 2-thienylalanine

Pep = 4-chlorophenylalanine

Bth = 3-benzothienyalanine Bip = 4,4'-biphenylalanine

Tic = tetrahydroisoquinoline-3-carboxylic acid

Aib = aminoisobutyric acid

Anb = α-aminonormalbutyric acid Dip = 2 ,2-diphenylalanine Thz = 4-Thiazolylalanine

The compounds of the present invention can be provided in the form of pharmaceutically acceptable salts. Examples of preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, trifluoroacetic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids, such as hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid and the like.

In another aspect, the invention features one of the above compounds and a pharmaceutically acceptable carrier substance in a therapeutic composition capable of decreasing excess intestinal water and electrolyte secretion.

In preferred embodiments, the composition is in the form of a liquid, pill, tablet, or capsule for oral administration; a liquid capable of being administered nasally as drops or spray or a liquid for intravenous, subcutaneous, parenteral, intraperitoneal or rectal administration. The therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration. For maximum efficacy, zero-order release is desired.

In another aspect the invention features, a method for decreasing excess intestinal water and electrolyte secretion in a mammal, the method comprising administering to the mammal, e.g., a human, a therapeutically effective amount of the above mentioned compounds .

In addition, the invention features a method of regulating cell proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the composition of the above mentioned compounds. Preferably, the method regulates the proliferation of an intestinal cell.

The invention also features methods for increasing nutrient transport, regulating lipolysis, and regulating blood flow in a mammal, the methods comprising administering to the mammal a therapeutically effective amount of the above mentioned compositions.

The compounds of the invention exhibit a broad range of biological activities related to their antisecretory and antimotility properties. The compounds are believed to suppress gastrointestinal secretions by direct interaction with epithelial cells or, perhaps, by inhibiting secretion of hormones or neurotransmitters which stimulate intestinal secretion. The compounds of the invention may also control intestinal blood flow which in turn may modulate intestinal hydrostatic pressure in favor of net water absorption.

The compounds of the invention are especially useful in the treatment of any number of gastrointestinal disorders (see e.g., Harrison 's Principles of Internal Medicine , McGraw-Hill Inc., New York, 12th Ed.) that are associated with excess intestinal electrolyte and water secretion as well as decreased absorption, e.g., infectious (e.g., viral or bacterial) diarrhea, inflammatory diarrhea, short bowel syndrome, or the diarrhea which typically occurs following surgical procedures, e.g., ileostomy. Examples of infectious diarrhea include, without limitation, acute viral diarrhea, acute bacterial diarrhea (e.g., salmonella, campylobacter , and clostridium or due to protozoal infections), or traveller's diarrhea (e.g., Norwalk virus or rotavirus) . Examples of inflammatory diarrhea include, without limitation, malabsorption syndrome, tropical spue, chronic pancreatitis, Crohn's disease, diarrhea, and irritable bowel syndrome. It has also been discovered that the peptides of the invention can be used to treat an emergency or life-threatening situation involving a gastrointestinal disorder, e.g., after surgery or due to cholera. Furthermore, the compounds of the invention can be used to treat patients suffering from Acquired Immune Deficiency Syndrome (AIDS) , especially during cachexia.

The compounds of the invention are also useful for inhibiting small intestinal fluid and electrolyte secretion, augmenting nutrient transport — as well as increasing cell proliferation — in the gastrointestinal tract, regulating lipolysis in, e.g, adipose tissue, and regulating blood flow in a mammal. The compounds of the invention are advantageous because they are truncated versions of the natural PYY peptide; thus, the shorter peptide not only facilitates easier synthesis and purification of the compounds, but also improves and reduces manufacturing procedures and expenses. Moreover, a shorter PYY compound is advantageous because such peptides will interact solely with PYY receptors and not with homologous receptors such as NPY Yl and Y3 ; thus, minimizing unwanted agonist or antagonist side reactions. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Detailed Description The drawings will first be described. Drawings

FIG. 1 shows a semipreparative reversed phase chromatogram of N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ. ID. NO. 3) («25mg) obtained by HF cleavage. Conditions: Vydac C18 semipreparative column (250 X 10mm, 300 A pore size, 10 micron particle size); flow rate 4.7 ml/min; fractions 1, 2, 3, and 4 were collected and analyzed by analytical chromatography. The homogeneous fractions (1-3) were combined and dried in a speed vac.

FIG. 2 shows a graph of the inhibition of ¹²⁵i- PYY binding to rat jejunal membranes by increasing concentrations of PYY (SEQ. ID. NO. 1), PYY (22-36) (SEQ. ID. NO. 10), [Im-DNP-His²⁶]PYY (SEQ. ID. NO. 9),

[Ala³²]PYY(22-36) (SEQ. ID. NO. 11), [Ala²³' ³² ]PYY (22-36) (SEQ. ID. NO. 12), [Glu²⁸] PYY (22-36) (SEQ. ID. NO. 13), N- α-Ac-PYY (22-36) (SEQ. ID. NO. 14), N-α-Ac- [p. Cl- Phe²⁸]PYY(22-36) (SEQ. ID. NO. 15), N-α-Ac- [Glu²⁶] PYY (22- 36) (SEQ. ID. NO. 16), N-α-Ac- [Phe²⁷]PYY (22-36) (SEQ. ID. NO. 3), N-α-Ac- [N-Me-Tyr²⁶] PYY (22-36) (SEQ. ID. NO. 17), N- α-Myristoyl-PYY (22-36) (SEQ. ID. NO. 18), N-α- Naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19), and PYY (22-26) (SEQ. ID. NO. 10) . FIGS. 3A-B show the antisecretory effects of PYY (SEQ. ID. NO. 1), PYY(22-36) (SEQ. ID. NO. 10) and analogs up one baseline short circuit current (SCC) in voltage clamped preparation of rat jejunum. Values of changes in SCC are quoted of μA/0.6cm², mean ±SEM from between 3 and 7 different jejunal preparations. Peptides shown in A and B are denoted by the same symbol as in FIG. 2.

FIG. 4 shows a graph of the inhibition of ¹²⁵I-PYY binding to rat jejunal membranes by increasing concentrations of PYY, N-α-Ac-PYY (22-36) (SEQ. ID. NO. 14), N-α-Ac-[Tic²⁷]PYY(22-36) (SEQ. ID. NO. 25), N-α-Ac- [Bip²⁷]PYY(22-36) (SEQ. ID. NO. 22), N-α-Ac- [Nal²⁷]PYY (22- 36) (SEQ. ID. NO. 23), N-α-Ac- [Bth²⁷]PYY (22-36) (SEQ. ID. NO. 21), N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ. ID. NO. 3), N-α-Ac- [Phe²⁷]PYY(25-36) (SEQ. ID. NO. 26), N-α-Ac- [Trp²⁷] PYY (22- 36) (SEQ. ID. NO. 5), and N-α-Ac- [Thi²⁷]PYY (22-36) (SEQ. ID. NO. 6) .

There now follows a description of the synthesis, analysis for biological efficacy and use of the preferred embodiments of the invention. In order to determine the structural requirements necessary to elicit antisecretory effects, several analogs of the PYY active site, PYY (22- 36) , were synthesized and their binding and antisecretory potencies in rat jejunum were compared.

We now describe the structure, synthesis, and use of preferred embodiments of the invention.

STRUCTURE

The peptides of the invention have the general formula recited in the Summary of the Invention above. They all have an aromatic amino acid group at position 27 which is important for both antisecretory activity and utility as antidiarrheal compounds.

SYNTHESIS

The peptides of the present invention may be synthesized by any techniques that are known to those skilled in the peptide art. An excellent summary of the many techniques so available may be found in Solid Phase Peptide Synthesis 2nd ed. (Stewart, J.M. and Young, J. D. Pierce Chemical Company, Rockford, IL, 1984) .

The peptides listed in Table 1 and Table 2 were synthesized as follows. Peptide synthesis was performed on an Applied Biosystems Model 430A synthesizer. Amino acid and sequence analyses were carried out using Waters Pico-Tag and Applied Biosystems Model 470A instruments, respectively. Peptides were purified using a Waters Model 600 solvent delivery system equipped with a Model 481 Spectrophotometer and U6K injector according to standard protocols. Peptide masses were determined at the University of Michigan, Protein Chemistry Facility, Ann Arbor, Michigan according to standard methods. All Boc-L-amino acid derivatives, solvents, chemicals and the resins were obtained commercially and used without further purification. Paramethylbenzhydroxyla ine (MBHA) resin (0.45 mmol, -NH₂) was placed in the reaction vessel of the peptide synthesizer and the protected amino acid derivatives were sequentially coupled using the program provided by the manufacturers modified to incorporate a double coupling procedure (see, e.g., Balasubramaniam et al., Peptide Research 1: 32, 1988). All amino acids were coupled using 2.2 equivalents of preformed symmetrical anhydrides. Arg, Gin and Asn, however, were coupled as preformed 1-hydroxybenzotriazole (HOBT) esters to avoid side reactions. At the end of the synthesis, the N-α-Boc group was removed and in some instances the free α-NH2 was acetylated by reaction with acetic anhydride (2 equivalents) and diisopropyl ethylamine until a negative ninhydrin test was obtained (Anal. Biochem. 34:595, 1970). The peptide resin (-1.0 g) was then treated with HF (10 ml) containing p-cresol (-0.8 g) for 1 h at -2 to -4 °C. The HF was evacuated and the residue was transferred to a fritted filter funnel with diethyl ether, washed repeatedly with diethyl ether, extracted with acetic acid (2 X 15 ml) and lyophilized. The crude peptides thus obtained were purified by semipreparative RP-HPLC as shown in Fig. 1.

Examples of the synthesized analogs are:

[im-DNP-H i s²⁶] PYY _, YPAKPEAPGEDASPEELSRYYASL [im-DNP-His"^>] YLNLVTRQRY-NH₂ (SEQ. ID No. 9)

PYYC22-36) A S L R H Y L N L V T R Q R Y-NH, (SEQ. ID No. 10)

[Ala³²] PYY

A S L R H Y L N L V [Ala] R Q R Y-NH, (SEQ. ID No. 11)

[A I a²³'³²] PYY A [Ala] L R H Y L N L V [Ala] R Q R Y-NH- (SEQ. ID No. 12)

[Glu²⁸]PYY(22-36)

A S L R H Y [Glu] N L V T R Q R Y-NH₂ (SEQ. ID No. 13)

N-α-Ac-PYY(22-36)

N-a-Ac-A S L R H Y L N L V T R Q R Y-NH (SEQ. ID No. 14) N-α-Ac [p. Cl. Phe²⁶] PYY

N-α-Ac-A S L R [p.Cl.Phe „2^c6^o _n] Y L N L V T R Q R Y-NH- (SEQ. ID No. 15)

N-α-Ac[Glu²⁸]PYY

N-α-Ac-A S L R H Y [Glu] N L V T R Q R Y-NH, (SEQ. ID No. 16)

N-α-Ac [Phe²⁷] PYY

N-α-Ac-A S L R H [Phe] E N L V T R Q R [N-Me-Tyr] -NH- (SEQ. ID No. 3)

N-α-Ac [N-Me-Tyr³⁶] PYY

N-α-Ac-A S L R H Y E N L V T R Q R [N-Me-Tyr] -NH₂ (SEQ. ID No. 17)

N-α-myristoyl-PYY(22-36)

N-α-myristoyl-A S L R H Y L N L V T R Q R Y- H₂ (SEQ. ID No. 18) N-α-naphthaleneacetyl -PYY(22-36)

N-α-naphthaleneacetyl -A S L R H Y L N L V T R Q R Y-NH₂ (SEQ. ID No. 19)

N-α-Ac [Phe²⁷] PYY

N-α-Ac-A S L R H [Phe] E N L V T R Q R [N-Me-Tyr] - H₂ (SEQ. ID No. 3)

N-α-Ac-PYY(22-36) N-α-Ac-A S L R H Y L N L V T R Q R Y-NH₂ (SEQ. ID No. 20)

N-α-Ac- [Bth²⁷]PYY(22-36)

N-α-Ac-A S L R H [Bth] L N L V T R Q R Y-NH₂ (SEQ. ID No. 21)

N-α-Ac- [Bip²⁷]PYY(22-36)

N-α-Ac-A S L R H [Bip] L N L V T R Q R Y-NH₂ (SEQ. ID No. 22) N-α-Ac- [Nal²⁷]PYY(22-36)

N-α-Ac-A S L R H [Nal] L N L V T R Q R Y-NH, (SEQ. ID No. 23)

N-α-Ac- [Trp ⁷]PYY(22-36)

N-α-Ac-A S L R H [Trp] L N L V T R Q R Y-NH₂ (SEQ. ID No. 5)

N-α-Ac- [Thi ⁷]PYY(22-36) N-α-Ac-A S L R H [Thi] L N L V T R Q R Y-NH-, (SEQ. ID No. 6)

N-α-Ac- [Tι^"c²⁷]PYY(22-36)

N-α-Ac-A S L R H [Tic] L N L V T R Q R Y-NH-, (SEQ. ID No. 25)

N-α-Ac- [Phe ⁷]PYY(25-36)

N-α-Ac-H [Phe] L N L V T R Q R Y-NH₂ (SEQ. ID No. 26) N-α-Ac- [Phe²⁷,Thi³⁶]PYY(22-36)

N-α-Ac-A S L R H [Phe] L N L V T R Q R [Thi] -NH-, (SEQ. ID No. 27)

N-α-Ac- [Thz²⁶,Phe²⁷]PYY(22-36)

N-α-Ac-A S L R [Thz] [Phe] L N L V T R Q R Y-NH₂ (SEQ. ID No. 28)

N-α-Ac- [Pcp²⁷]PYY(22-36) N-α-Ac-A S L R H [Pep] L N L V T R Q R Y-NH₂ (SEQ. ID No. 29)

N-α-Ac- [Phe^22,27] PYY(22-36)

N-α-Ac- [Phe] S L R H [Phe] L N L V T R Q R Y-NH, (SEQ. ID No. 30) N-α-Ac- [Tyr²²,Phe²⁷]PYY(22-36)

N-α-Ac- [Tyr] S L R H [Phe] L N L V T R Q R Y-NH₂ (SEQ. ID No. 7)

N-α-Ac- [Trp²⁸]PYY(22-36)

N-α-Ac- A S L R H Y [Trp] N L V T R Q R Y-NH₂ (SEQ. ID No. 31) N-α-Ac- [Trp³⁰] PYY(22-36)

N-α-Ac- A S L R H Y L N [Trp] V T R Q R Y-NH₂ (SEQ. ID No. 32)

N-α-Ac- [Ala²⁶, Phe²⁷] PYY(22-36)

N-α-Ac- A S L R [Ala] [Phe] L N L V T R Q R Y-NH₂ (SEQ. ID No. 33)

N-α-Ac- [Bth²⁷]PYY(22-36) N-α-Ac- A S L R H [Bth] L N L V T R Q R Y-NH₂ (SEQ. ID No. 34)

N-α-Ac- [Phe²⁷]PYY(22-36)

N-α-Ac- A S L R H [Phe] L N L V T R Q R Y-NH₂ (SEQ. ID No. 35)

N-α-Ac- [Phe²⁷'³⁶]PYY(22-36)

N-α-Ac- A S L R H [Phe] L N L V T R Q R [Phe]-NH₂ (SEQ. ID No. 36) N-α-Ac- [Phe²⁷, D-Trp³ ]PYY(22-36)

N-α-Ac- A S L R H [Phe] L N L V [D-Trp] R Q R Y-NH₂ (SEQ. ID No. 37)

ANALYSIS

Binding Studies

Preparation of ¹²⁵I-PYY labeled only at Tyr³⁶ and rat jejunal epithelial plasma membranes were performed according to standard methods (see, e.g., Laburthe et al.

Endocrinology, supra; Servin et al. supra; Voisin et al.

Ann. N. Y. Acad. Sci. 611:343, 1990). Binding experiments were conducted in a total volume of 0.25 ml 60 mM HEPES buffer, pH 7, containing 2% BSA, 0.1% bacitracin, 5 mM MgCl₂ and 0.05 nM ¹²⁵ι-pγγ with or without competing peptides. Bound and free peptides were separated by centrifugation at 20,000 X g for 10 min.

Non-specific ¹²⁵I-PYY binding was determined in the presence of 1 μM unlabeled PYY represented 10% of the total binding.

Short Circuit Current Measurements

The antisecretory effects of the peptides were investigated by measuring the short-circuit current (SCC) in rat jejunal mucosa mounted in a Ussing chamber and automatically voltage clamped as described by Cox et al.

(J^". Physiol. supra). Briefly, strips of mucosa were placed between two halves of perspex Ussing chambers (window size, 0.6 cm²) containing oxygenated (95% 0₂/5% C0₂) Krebs-Henseleit solution (NaCl, 117 mM, KC1 4.7 mM, CaCl₂, 2.5 mM; MgS0₄ 1.2 mM, NaHC0₃ 24.8 mM and glucose 11.1 mM) , pH 7.4, 37°C. Routinely, four preparations of jejunum were obtained from each animal and these exhibited comparable potential differences and SCC, but they were not paired. Preparations were automatically voltage clamped using a W-P dual voltage clamp and the SCC displayed continuously on pen recorders. Once a stable baseline SCC was reached, peptides were added to the basolateral reservoir only, and cumulative concentration-response profiles constructed. Data Analyses All points in the binding experiments are the mean of at least three experiments performed in duplicate.

For clarity, the SEMs in the binding experiments are not shown in Fig. 2, but were less than 10%. Values of changes in SCC are quoted as μA/0.6cm² mean ± 1 SEM from between 3 and 7 different preparations. EC₅₀ values were calculated from pooled cumulative concentration - response curves using an iterative curve fitting program. Comparison of data groups (SCC recordings) were made using unpaired Student's t-tests where a p value <0.5 was considered statistically significant. There now follows the results of the biological activities of the compounds of the invention (see Table 1 and Table 2) . As described below, the tested compounds were assayed for purity and for their binding and antisecretory potencies in rat jejunum. Purified peptides were found to be > 96% homogeneous by analytical reversed phase chromatography and, in addition, had the expected amino acid composition and masses. For example, Fig. 1 shows the RP-HPLC chromatogram of N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ. ID. NO. 3). The free peptides were further characterized by sequence analysis (see, Table 1 and Table 2) . The overall yields of the peptides were in the range of 10% to 30%.

PYY, [im-DNP-His²⁶]PYY (SEQ. ID. NO. 9) and the analogs of PYY (22-36) (SEQ. ID. NO. 10) displaced ¹²⁵I-PYY bound to rat jejunal epithelial plasma membranes in a concentration-dependent manner. Although [ im-DNP- His²⁶]PYY (SEQ. ID. NO. 9) and PYY(22-36) (SEQ. ID. NO. 10) were 20-times less potent than PYY based on IC₅₀ values, they displayed the same maximal response as the intact hormone (Fig. 2, Table 1). Substitution of Thr³² with Ala as in [Ala³²]PYY(22-36) (SEQ. ID. NO. 11) resulted in the lowering of the binding potency while the replacement of both Ser²³ and Thr³² with Ala further reduced the receptor affinity. Also, introduction of a negative charge at position 28 without altering the helicity as in [Glu ⁸]PYY (22-36) (SEQ. ID. NO. 13) decreased the binding possibly due to the disruption of the ionic interactions. Since the hydrophobic groups are known to increase the interaction with the receptors (Balasubramaniam et al. Biochem . Biophys . Res . Comm .

137:1041, 1986), the binding of a N-α-myristoyl- and N-α- naphthaleneacetyl-derivatives of PYY (22-36) was also determined. Both these analogs exhibited slightly lower binding affinity than PYY (22-36) (SEQ. ID. NO. 10) possibly due to increased steric hinderance. On the other hand, N-α-acetylation of PYY (22-36) (SEQ. ID. NO. 14) increased the receptor affinity four times. Further structure-activity studies with N-α-Ac-PYY (22-36) (SEQ. ID. NO. 20) revealed that substitution of Tyr³⁶ with N-Me- Tyr or His²⁶ with p.Cl-Phe lowers the binding potency. However, replacement of Tyr²⁷ with Phe increased the receptor affinity by 28%. As a control, the binding of PYY (22-36) (SEQ. ID. NO. 10) and several of its analogs were also tested. However, none of these analogs inhibited the binding of ¹²⁵I-PYY even at 10 μM. In mucosal preparations of rat jejunum PYY (22-36) (SEQ. ID. NO. 10) analogs reduced the baseline SCC in a concentration dependent manner (Fig. 3A and B) and calculated EC₅₀ values are listed in Table 1. The PYY (22- 36) (SEQ. ID. NO. 10) analogs were generally less potent as antisecretory agents than as inhibitors of binding. The order of analog potency was similar to that from binding studies with two notable exceptions, namely N-α- myristoyl-PYY (22-36) (SEQ. ID. NO. 18) and N-α- naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19). N-α- acetylation and substitution of Tyr²⁷ with Phe increased the antisecretory potency of PYY (22-36) and this analog, N-α-Ac- [Phe²⁷] PYY(22-36) (SEQ. ID. NO. 3), was only 9- times less potent than the intact hormone. Furthermore, there was no significant difference between the maximal inhibitory responses, these being - 12.6±2.4 and - 12.0±1.3μ A/0.6cm² for PYY (440 nM, n = 6) (SEQ. ID. NO. 1) and N-α-Ac- [Phe²⁷] PYY(22-36) (1.4 μM, n = 7) (SEQ. ID. NO. 3) , respectively.

TABLE 1: Comparison of the binding and antisecretory potencies of PYY, PYY fragments and their analogs

PEPTIDES RT^d MH+ (Calc.) BINDING¹" SCC^L (min) IC₅₀(nM) EC_5Q(nM)

a: isocratic, 27% CH,CN containing 0.1% TFA; b: mean of three separate experiments; c: isocratic, 32% CH--CN containing 0.1% TFA; d: from reference 10; n.d.: not determined

N-α-myristoyl-PYY (22-36) (SEQ. ID. NO. 18) and N-α- naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19) analogs, in contrast to their moderate binding potency, exhibited poor antisecretory responses with threshold 5 concentrations of about 20nM and EC₅₀ values greater than 2 and 30 μM respectively. After a cumulative concentration of 7.4 μM, N-α-myristoyl-PYY (22-36) (SEQ. ID. NO. 18) reduced the basal SCC by - 5.2±0.6μA/0.6cm² (n = 7) . Subsequent addition of PYY (100 nM) further lθ reduced the SCC by

-10.2±0.7μA/0.6cm² (n = 7) and this was not significantly different from control responses to PYY (22-36) (SEQ. ID. NO. 10) could antagonize PYY responses, three tissues were treated with the analog (lμM) and PYY concentration-

15 response curves were constructed and compared with controls. The fragment reduced the basal current by - 0.4±0.3 μA/0.6cm² and the resultant PYY EC₅₀ value (4.4±1.2 nM, n = 3) did not differ significantly from that of the nontreated controls (2.6±1.1 nM, n = 3).

20 These results show that modification of the active site of PYY (SEQ. ID. NO. 1), PYY (22-36) (SEQ. ID. NO. 10) , can lead to a substantial increase in both the binding and antisecretory potencies of this fragment. The key analogs in this series exhibited the following

25 order of potency: PYY (SEQ. ID. NO. 1) > N-α-Ac-

[Phe²⁷]PYY(22-36) (SEQ. ID. NO. 3) > N-α-Ac-PYY (22-36) (SEQ. ID. NO. 14) > PYY(22-36) (SEQ. ID. NO. 10). Furthermore, our investigations revealed that the hydroxyl groups of Ser²³ and Thr³² as well as the imidazole group of His²⁶

30 are important for interaction with intestinal PYY- preferring receptors. Although there was, in general, a good correlation between the binding and antisecretory potencies of the analogs, there were also notable exceptions. N-α-myristoyl-PYY (22-36) (SEQ. ID. NO. 18) and N-α- naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19) analogs inhibited ¹²⁵I-PYY binding with moderate potency, but exhibited poor antisecretory responses. This observation suggested that these analogs may be antagonists.

However, prior pretreatment of jejunal membranes with these analogs failed to significantly alter the antisecretory responses to PYY and the reason for the discrepancy remains unclear at present. Table 2 and Fig. 4 present the IC₅₀ values for additonal PYY(22-36) (SEQ. ID. NO. 10) and PYY (25-36) analogs. Based on the results presented in Table 2 the analogs in this series exhibited the following order of potency: N-α-Ac-[Tic²⁷]PYY(22-36) (SEQ. ID. NO. 25) < N-α-Ac- [Bip²⁷]PYY(22-36) (SEQ. ID. NO. 22) < N-α-Ac- [Nal²⁷]PYY(22-36) (SEQ. ID. NO. 23) < N-α-Ac- [Bth²⁷]PYY(22-36) (SEQ. ID. NO. 21) < N-α-Ac- [Phe²⁷]PYY(22-36) (SEQ. ID. NO. 3) < N-α-Ac- [Phe²⁷] PYY (25- 36) (SEQ. ID. NO. 26) < N-α-Ac- [Trp²⁷]PYY (22-36) (SEQ. ID. NO. 5) < N-α-Ac-[Thi²⁷]PYY(22-36) (SEQ. ID. NO. 6) < N-α- Ac-PYY (22-36) (SEQ. ID. NO. 14) < PYY (SEQ. ID. NO. 1).

TABLE 2 Comparison of Receptor Binding Data for PYY and PYY analogs

NPY/PYY receptors characterized to date have been broadly classified into Y-l, Y-2 and Y-3 subtypes (Balsubramaniam et al. J . Biol . Chem . 265:14724, 1990; Michel, Trends Pharmacol . Sci . 12:389, 1991). Both Y-l and Y-2 receptors exhibit a preference for PYY over NPY, and more significantly C-terminal fragments of NPY and PYY are effective only at the Y-2 subtype. Y-3 receptors, on the other hand, exhibit a greater affinity for NPY than PYY. Since rat jejunal mucosa antisecretory responses show an order of agonist potency PYY (SEQ. ID. NO. 1)> NPY (SEQ. ID. NO. 24) > PYY (13-36) (SEQ. ID. NO. 32) > NPY(13-36) (SEQ. ID. NO. 33) these epithelial receptors are Y-2 like, and are completely insensitive to the Y-l selective agonist [Pro³ ]NPY (Cox et al. Peptides, supra) . The results further describe N-α-Ac-PYY (22-36) (SEQ. ID. NO. 14) and N-α-Ac-[Phe²⁷]PYY(22-36) (SEQ. ID. NO. 3) to be more potent than PYY (22-36) (SEQ. ID. NO. 10) and the corresponding C-terminal fragments of NPY of varying lengths (Cox et al. Br . J . Pharmacol , supra) . The higher affinity for PYY (SEQ. ID. NO. 1) and its C- terminal fragments compared with NPY (SEQ. ID. NO. 24) and its respective fragments is in agreement with the order of potency obtained from receptor binding studies with rat intestinal epithelial membranes (Laburthe et al. supra ; Laburthe, supra ; Voisin et al. Ann . N. Y . Acad . Sci . supra ; Voisin et al. Am. J^". Physiol . )

In addition, analogs listed in Table 3 were synthesized as described above and tested for binding activity. The results shown in Table 3 demonstrate that N-α-Ac- [Tyr²², Phe²⁷]PYY (22-36) (SEQ. ID. NO. 7) is similar in its competitive binding as PYY (SEQ. ID. NO. 1) , indicating that the introduction of an aromatic amino acid, e.g., Tyr, at position 22 is an effective PYY analog.

TABLE 3

USE

In the practice of the method of the present invention, an effective amount of an any one or combination of the analogs of the invention, e.g. , N-α- Ac-[Phe²⁷]PYY(22-36) (SEQ. ID. NO. 3), N-α-Ac-

[Trp²⁷]PYY(22-36) (SEQ. ID. NO. 24), N-α-Ac- [Phe²⁷] PYY (25- 36) (SEQ. ID. NO. 3), N-α-Ac- [Thi²⁷] PYY (22-36) (SEQ. ID. NO. 6) or derivative thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention. These compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously) , rectally ( e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or either solid, liquid or gaseous dosage, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.

Thus, the method of the present invention is practiced when relief of symptoms is specifically required or perhaps imminent. Alternatively, the method of the present invention is effectively practiced as continuous or prophylactic treatment.

Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid- protein vesicles) , sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulation for intravenous administration comprise sterile aqueous solutions of the active ingredient (s) which are prepared by dissolving solid active ingredient (s) in water to produce an aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington 's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

The dose of the compound of the present invention for treating the above-mentioned disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount". Thus, a typical administration is oral administration or parenteral administration. The daily dose in the case of oral administration is typically in the range of 0.1 to 100 mg/kg body weight, and the daily dose in the case of parenteral administration is typically in the range of 0.001 to 50 mg/kg body weight.

To be effective for the prevention or treatment of gastroenterological disorders, especially infectious (e.g. viral or bacterial) or inflammatory diarrhea, or diarrhea resulting from surgery, it is important that the therapeutic agents be relatively non-toxic, non-antigenic and non-irritating at the levels in actual use.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

SEQUENCE LISTING (1) GENERAL INFORMATION (i) APPLICANT: UNIVERSITY OF CINCINNATI (ii) TITLE OF THE INVENTION: ANALOGS OF PEPTIDE YY AND USES

THEREOF

(iii) NUMBER OF SEQUENCES: 30

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: Fish & Richardson P.C.

(B) STREET: 225 Franklin Street

(D) STATE: MA

(E) COUNTRY: US

(F) ZIP: 02110-2804

(v) COMPUTER READABLE FORM:

( A MEDIUM TYPE: Diskette

( B COMPUTER: IBM Compatible

( C OPERATING SYSTEM: DOS

( D SOFTWARE: FastSEQ Version 2.0

(vi ) CURRENT APPLICATION DATA:

( A APPLICATION NUMBER:

( B FILING DATE: 13-NOV-1996

( C CLASSIFICATION:

( viii) ATTORNEY/AGENT INFORMATION:

( A NAME: Tsao, Y. Rocky

( B REGISTRATION NUMBER: 34,476

( C REFERENCE/DOCKET NUMBER: 00537/105WO1

( ix ) TELECOMMUNICATION INFORMATION:

( A TELEPHONE: 617-542-5070

( B TELEFAX: 617-542-8906

( C TELEX:

(2) INFORMATION FOR SEQ ID Nθ:l:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:l:

Tyr Pro Ala Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu

1 5 10 15

Leu Ser Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr

20 25 30

Arg Gin Arg Tyr 35

(2) INFORMATION FOR SEQ ID NO: 2:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 amino acids

(B) TYPE: amino acid

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:

Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu

1 5 10 15

Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr

20 25 30

Arg Gin Arg Tyr 35

(2) INFORMATION FOR SEQ ID NO: 3:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa in position 15 is an abbreviation of N-Me-Tyr. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:

Ala Ser Leu Arg His Phe Leu Asn Leu Val Thr Arg Gin Arg Xaa 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 4:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:

Ala Ser Leu Arg His Phe Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 5:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(ii) MOLECULE TYPE: None

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has an acetylated N- terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N- ). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:

Ala Ser Leu Arg His Trp Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 6:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( i ) FEATURE :

(D) OTHER INFORMATION: Xaa in position 6 is an abbreviation of Thi (2-thienylalanine) . The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-) . The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:

Ala Ser Leu Arg His Xaa Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 7:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7:

Tyr Ser Leu Arg His Phe Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 8:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:8:

Arg His Phe Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10

(2) INFORMATION FOR SEQ ID NO: 9:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: Xaa in position 26 is an abbreviation of im-DNP-His. The sequence has an acetylated N- terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N- ). The sequence has an amide C-terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:9:

Tyr Pro Ala Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu

1 5 10 15

Leu Ser Arg Tyr Tyr Ala Ser Leu Arg Xaa Tyr Leu Asn Leu Val Thr

20 25 30

Arg Gin Arg Tyr 35

(2) INFORMATION FOR SEQ ID NO: 10:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has an amide C- terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:ll:

Ala Ser Leu Arg His Tyr Leu Asn Leu Val Ala Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 12:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(D) OTHER INFORMATION: The sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:

Ala Ala Leu Arg His Tyr Leu Asn Leu Val Ala Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 13:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13:

Ala Ser Leu Arg His Tyr Glu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14:

Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 15:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa in position 5 is an abbreviation of p.Cl.Pro. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:

Ala Ser Leu Arg Xaa Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 16:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D ) TOPOLOGY : 1inear

(ix) FEATURE:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

Ala Ser Leu Arg His Tyr Glu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

Ala Ser Leu Arg His Tyr Glu Asn Leu Val Thr Arg Gin Arg Xaa 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 18:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(D) OTHER INFORMATION: The sequence has a myristoylated N-terminus (i.e., N-α-myristoyl) , rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:18:

Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 19:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has a napthalenoacetyl N-terminus (i.e., N-α-napthaleneacetyl) , rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., C0- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:

Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15 (2) INFORMATION FOR SEQ ID NO: 20:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:

Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 21:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa in position 6 is an abbreviation of Bth. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide c-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21:

Ala Ser Leu Arg His Xaa Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: Xaa in position 6 is an abbreviation of Bip. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Ala Ser Leu Arg His Xaa Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 23:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: Xaa in position 6 is an abbreviation of Nal. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:

Ala Ser Leu Arg His Xaa Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: The sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO- OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:

Tyr Pro Ser Lys Pro Asp Asn Pro Gly Glu Asp Ala Pro Ala Glu Asp

1 5 10 15

Met Ala Arg Tyr Tyr Ser Ala Leu Arg His Tyr lie Asn Leu lie Thr

20 25 30

Arg Gin Arg Tyr 35

(2) INFORMATION FOR SEQ ID NO: 25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(D) OTHER INFORMATION: Xaa in position 6 is an abbreviation of Tic. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:

Ala Ser Leu Arg His Xaa Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 26:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE :

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:

His Phe Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10

(2) INFORMATION FOR SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( i ) FEATURE:

(D) OTHER INFORMATION: Xaa in position 15 is an abbreviation of Thi. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:

Ala Ser Leu Arg His Phe Leu Asn Leu Val Thr Arg Gin Arg Xaa 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 28:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

( ix ) FEATURE : (D) OTHER INFORMATION: Xaa in position 15 is an abbreviation of Thz. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH).

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28:

Ala Ser Leu Arg Xaa Phe Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 29:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D ) TOPOLOGY : 1inear

( ix) FEATURE :

(D) OTHER INFORMATION: Xaa in position 6 is an abbreviation of Pep. The sequence has an acetylated N-terminus (i.e., N-α-Ac), rather than an amino N-terminus (i.e., H2N-). The sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:

Ala Ser Leu Arg His Xaa Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

(2) INFORMATION FOR SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(D) TOPOLOGY: linear

(ix) FEATURE:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:

Phe Ser Leu Arg His Phe Leu Asn Leu Val Thr Arg Gin Arg Tyr 1 5 10 15

What is claimed is:

Claims

1. A compound having the formula: ^Rι ^R3

_R2^_X__A22__A23__A24__A25__A26__A27__A28__A29__A30__A31__A32__Y._R4

wherein

X is Cys or is deleted;

Y is a chain of 0-4 amino acids, inclusive, the C-terminal one of which is bonded to R₃ and R₄;

R_χ is H, C-_L-C-_L2 alkyl, C₆-C₁₈ aryl, C^C-^ acyl, ^C ₇~ ₁₈ aralkyl or C₇-C₁₈ alkaryl;

R₂ is H, C₁-C₁₂ alkyl, C₆-C₁₈ aryl, C₁-C₁₂ acyl,

C₇-C₁₈ aralkyl, or C₇-C₁₈ alkaryl; A²² is an aromatic amino acid, Ala,

Aib, Anb, N-Me-Ala, or is deleted; A²³ is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N- Me- Ala, D-Trp, or is deleted;

A²⁴ is Leu, Gly, lie, Val, Trp, Nle, Nva, Aib, Anb,

N-Me-Leu, or is deleted; A²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain ^C-^_Q alkyl group, or an aryl group) , Orn or is deleted; A²⁶ is Ala, His, Thr, 3-Me-His, 1-Me-His, /?-pyrozolylalanine, N-Me-His, Arg, Lys, homo-

Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched chain or straight chain C^C-^ alkyl group, or an aryl group), Orn, or is deleted; A²⁷ is an aromatic amino acid other than Tyr; A²⁸ is Leu, Val, Trp, Nle, Nva, Aib, Anb, or

N-Me-Leu; A²⁹ is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A³⁰ is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu; A³¹ is Val, Leu, lie, Trp, Nle, Nva, Aib, Anb, or

N-Me-Val; A³² is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R₃ is H, C-L-C-,^ alkyl, C₆-C₁₈ aryl, C^C-,^ acyl, C₇-

C₁₈ aralkyl, or C₇-C₁₈ alkaryl; and R₄ is H, C₁-C₁₂ alkyl, C₆-C₁₈ aryl, C^C-,^ acyl, C₇-

C₁₈ aralkyl, C₇-C₁₈ alkaryl, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A²⁷ is Phe, Nal, Bip, Pep, Tic, Trp, Trp, Bth, Thi, or Dip.

3. The compound of claim 1, where Y is A³³-A³⁴- A³⁵-A³⁶ wherein

A³³ is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C±-C±_Q alkyl group, or C₆-C₁₈ aryl group) , or Orn; A³⁴ is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Aib, or Anb; A³⁵ is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg,

Lys-e-NH-R (where R is H, a branched or straight chain C±-C±_Q alkyl group, or C₆-C₁₈ aryl group) , or Orn; and A³⁶ is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein said compound has the formula:

N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 3) , or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3 , wherein said compound has the formula:

H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln- Arg-Tyr-NH₂ (SEQ. ID. NO. 4) , or a pharmaceutically acceptable salt thereof.

6. The compound of claim 3, wherein said compound has the formula:

N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 5) , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 3 , wherein said compound has the formula:

N-α-Ac-Ala-Ser-Leu-Arg-His-Thi-Leu-Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 6) , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 3, wherein said compound has the formula:

N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val- Thr-Arg-Gln-Arg-Tyr-NH₂ (SEQ. ID. NO. 7) , or a pharmaceutically acceptable salt thereof.

9. A compound having the formula :

^Ri ^R3

\ /

R₂-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-Y-R₄

wherein the N-terminal amino acid is bonded to R_λ and R₂; Y is a chain of 0-4 amino acids, inclusive the C- terminal one of which is bonded to R₃ and R₄; R_χ is H, C-_L-C-_]^ alkyl, C₆-C₁₈ aryl, C-L-C.^ acyl,

C₇-C₁₈ aralkyl, or C₇-C₁₈ alkaryl; R₂ is H, C^C-^ alkyl, C₈-C₁₈ aryl, C-^-C^ ^acYlf C₇-C₁₈ aralkyl, or C₇-C₁₈ alkaryl; A²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C₁-C₁₀ alkyl group, or an aryl group) , Orn or is deleted; A²⁶ is Ala, His, Thr, 3-Me-His, 3-pyrozolylalanine, N-Me-His, Arg, Lys, homo-

Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) , or Orn; A²⁷ is an aromatic amino acid; A²⁸ is Leu, Val, Trp, Nle, Nva, Aib, Anb, or

N-Me-Leu; A²⁹ is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A³⁰ is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu; A³¹ is Val, Leu, lie, Trp, Nle, Nva, Aib, Anb, or

N-Me-Val; A³² is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R₃ is H, C-_L-C.,^ alkyl, C₆-C₁₈ aryl, C₁-C₁₂ acyl, C₇- C₁₈ aralkyl, or C₇-C₁₈ alkaryl; and R₄ is H, C-_|_- C₁₂ alkyl, C₆-C₁₈ aryl, C^-C^ acyl,

C₇-C₁₈ aralkyl or C₇-C₁₈ alkaryl, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein A²⁷ is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip.

11. The compound of claim 9, wherein Y is A³³-

_A34__A35__A36 _Wh_{ere n}

A³³ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or C₆-C₁₈ aryl group) , Cys, or Orn; A³⁴ is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Alb, or

Anb; A³⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C^C-,^ alkyl group, or C₆-C₁₈ aryl group) , Cys, or Orn; and A³⁶ is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, wherein said compound has the formula:

N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr- NH₂ (SEQ. ID. NO. 26) , or a pharmaceutically acceptable salt thereof.

13. A therapeutic composition capable of decreasing excess intestinal water and electrolyte secretion, said composition comprising a therapeutically effective amount of the compound of claim 1 or claim 9, together with a pharmaceutically acceptable carrier substance.

14. A method of decreasing excess intestinal water and electrolyte secretion in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the composition of claim 1 or claim 9, together with a pharmaceutically acceptable carrier substance.

15. A method of regulating cell proliferation in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the composition of claim 1 or claim 9, together with a pharmaceutically acceptable carrier substance.

16. A method of augmenting nutrient transport in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the composition of claim 1 or claim 9, together with a pharmaceutically acceptable carrier substance.

17. A method or regulating lipolysis in a mammal, said method comprising adminsitering to said mammal a therapeutically effective amount of the composition of claim 1 or claim 9, together with a pharmaceutically acceptable carrier substance.

18. A method of regulating blood flow in a mammal, said method comprising adminsitering to said mammal a therapeutically effective amount of the composition of claim 1 or claim 9, together with a pharmaceutically acceptable carrier substance.

19. A dimeric compound comprising either two peptides of claim 1 or claim 9, or one peptide of claim 1 or one peptide of claim 9 , wherein said dimer is formed by either an amide bond, or a disulfide bridge between said two peptides.

EP96942759A 1996-11-13 1996-11-13 Analogs of peptide yy and uses thereof Withdrawn EP1015007A1 (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
PCT/US1996/018374 WO1998020885A1 (en)	1996-11-13	1996-11-13	Analogs of peptide yy and uses thereof

Publications (1)

Publication Number	Publication Date
EP1015007A1 true EP1015007A1 (en)	2000-07-05

Family

ID=22256144

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP96942759A Withdrawn EP1015007A1 (en)	1996-11-13	1996-11-13	Analogs of peptide yy and uses thereof