Synthesis and pharmacological characterization of 3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindol-2-yl)ethyl]pyrido-[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (A-131701): A uroselective alpha(1A) adrenoceptor antagonist for the symptomatic treatment of benign prostatic hyperplasia

Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication, were originally developed as antihypertensives, and their ameliorative effects in the treatment of benign prostatic hyperplasia (BPH) were not observed until after their introduction into clinical practice. Consequently, these agents suffer from significant cardiovascular side effects when administered for the BPH indication. Tamsulosin5 (5), recently approved in Japan, is the first 'uroselective' α1 antagonist developed for the treatment of BPH (Figure 1). Within the past several years, the heterogeneity of the α1 receptor has been realized both on a molecular and pharmacological level. Three subtypes of the human α1 receptor have been cloned and expressed: α(1a), α(1b), and α(1d). In several studies antagonist blockade of norepinephrine- or phenylephrine-induced contraction of human prostate tissues has been found to correlate with affinity for the α(1a) subtype. Consequently, an agent which demonstrates selectivity for the α(1a) subtype may have efficacy in the treatment of BPH with significantly reduced cardiovascular side effects.