PT - JOURNAL ARTICLE AU - Alison Betts AU - Fidelma Atkinson AU - Iain Gardner AU - David Fox AU - Rob Webster AU - Kevin Beaumont AU - Paul Morgan TI - Impact of Physicochemical and Structural Properties on the Pharmacokinetics of a Series of α1<sub>L</sub>-Adrenoceptor Antagonists AID - 10.1124/dmd.107.015180 DP - 2007 Aug 01 TA - Drug Metabolism and Disposition PG - 1435--1445 VI - 35 IP - 8 4099 - http://dmd.aspetjournals.org/content/35/8/1435.short 4100 - http://dmd.aspetjournals.org/content/35/8/1435.full SO - Drug Metab Dispos2007 Aug 01; 35 AB - A rational drug discovery process was initiated to design a potent and prostate-selective α1L-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 α1L pA2 of 9.2 with 25-fold selectivity over rat aorta α1D) and sufficiently long elimination half-life in human volunteers (11–17 h) for once a day administration. The American Society for Pharmacology and Experimental Therapeutics