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Advances in the design and synthesis of prazosin derivatives over the last ten years - PubMed

Review

Advances in the design and synthesis of prazosin derivatives over the last ten years

Andreas Desiniotis et al. Expert Opin Ther Targets. 2011 Dec.

Abstract

Introduction: Mechanistic, translational and pharmacological studies led to the identification and discovery of the preferred localization, binding characteristics, structure and functional properties of α1-adrenoceptor (α1-AR) subtypes in the bladder neck, bladder and prostate gland. The evidence gathered on α1-ARs, provided a molecular platform for the development of subtype-selective antagonists, resulting in more effective approaches targeting those receptors for the treatment of outlet bladder obstruction and benign prostate hyperplasia.

Areas covered: Advances over the last decade in the design and optimization of Prazosin, Doxazosin and Terazosin quinazoline-based derivatives as α1-AR antagonists. Evidence on the metabolic and growth interference action by these agents, in addition to their smooth-muscle-relaxing effects. The new action recognition emerges from data on the inhibitory effect of quinazoline-based antagonists on primary tumor growth and progression to metastasis. In addition to the cellular findings in the prostate, functional validation and therapeutic effects of selected lead pharmaceutically optimized derivatives in the context of impairing vascularity and triggering tumor apoptosis.

Expert opinion: Knowledge on targeting intracellular signalling pathways driving the cellular response via an α1-AR-dependent and independent antagonistic action, must be invested towards the optimization of new agents that while bypassing AR, exhibit improved pharmacological efficacy against human cancer.

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Figures

Figure 1
Figure 1

Signaling pathways downstream of α1-AR activation. Activation of α1-ARs via agonistic binding of norepinephrine or mutations results in activation of Gα subunits and further activation of various effectors including PLC, PLA2, PLD, leading to induction of different transcription factors leading to heart diseases and possibly cancer [7].

Figure 2
Figure 2

Chemical structures of Prazosin and quinazoline α1-AR antagonistc derivatives Doxazosin, Terazosin, and Tamsulosin [98]. Those agents selectively antagonize the α1-AR mediated contraction of the prostate, prostatic capsule, proximal urethra and bladder base, and urinary symptoms associated with BPH. Recently, Doxazosin, Terazosin and their derivatives have affiliated as potential anti-cancer agents.

Figure 3
Figure 3

Chemical structures of the tyrosine kinase inhibitors Gefitinib (ZD1839) and Erlotinib (OSI-774) containing the quinazoline core. Both TKIs show promising results in preclinical and clinical studies in many human epithelial cancers, including HNSCC, NSCLC, CRC, breast cancer, pancreatic cancer and brain cancer, where aberrant expression or activity of EGFR has been identified as an important factor of cancer progression.

Figure 4
Figure 4

Strategies for structural modifications of doxazosin. A, B, C, and D indicate four modification strategies that target the 2,3-dihydro-benzo{1,4} dioxane moiety, the terminal acyl function, the piperazine linker, and the methoxy side chain ofthe quinazoline base, respectively leading to the synthesis of new Doxazosin derivatives with different properties [72].

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