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ABSTRACT:A rational drug discovery process was initiated to design a potent and prostate-selective ␣1 L -adrenoceptor antagonist with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of benign prostatic hyperplasia. Two series of compounds based on a quinoline or quinazoline template were identified with appropriate pharmacology. A series of high molecular weight cations with high hydrogen-bonding potential had extensive in vivo clearance, despite demonstrating metabolic stability. Studies in the isolated perfused rat liver and fresh rat hepatocytes indicated that active transport protein-mediated hepatobiliary elimination is an efficient clearance process for these compounds. A reduction in molecular weight and hydrogen-bonding potential resulted in a second series of compounds with in vivo hepatic clearance predictable from in vitro metabolic clearance. Initially, lipophilicity was reduced within this second series to reduce metabolic clearance and increase elimination half-life. However, this strategy also resulted in a concomitant reduction in volume of distribution and a negligible effect on prolonging half-life. An alternative strategy was to increase the intrinsic metabolic stability of the molecule by careful structural modifications while maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine side chain resulted in identification of UK-338,003, (N-[2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-methanesulfonamide), which fulfilled the objectives of the discovery program with suitable pharmacology (human prostate ␣1 L pA 2 of 9.2 with 25-fold selectivity over rat aorta ␣1 D ) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration.␣1-Adrenoceptor antagonists are well precedented in the effective treatment of both hypertension and benign prostatic hyperplasia (BPH); e.g., doxazosin (Fulton et al., 1995), terazosin (Jonler et al., 1994), and tamsulosin (Wilde and McTavish, 1996). However, because many of the ␣1-adrenoceptor antagonists clinically used in the treatment of BPH were originally developed for hypertension, they are nonselective for ␣1-adrenoceptor subtypes. These nonselective ␣1-adrenoceptor antagonists have similar efficacy and are generally well tolerated in BPH patients, but some patients experience dizziness and postural hypotension, which may be minimized by dose titration. It has been postulated that a drug that blocks the ␣1 L -adrenoceptor subtype would specifically target the prostate and thus have a better ratio of efficacy to safety, with fewer cardiovascular side effects than currently available nonselective ␣1-adrenoceptor antagonists.The aim of the drug discovery program was to identify a novel and potent ␣1 L -adrenoceptor antagonist that was functionally selective for the prostate gland over the cardiovascular system and thus have the potential to be effective in the treatment of BPH with fewer dose-limiti...