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

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.