Received for publication February 15, 2007.
Revised May 3, 2007.
Accepted for publication May 11, 2007.

Impact of Physicochemical and Structural Properties on the Pharmacokinetics of a Series of 1_L-adrenoceptor antagonists

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 following oral dosing, for the treatment of BPH. 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 whilst maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine sidechain resulted in identification of UK-338,003, which fulfilled the objectives of the discovery programme with suitable pharmacology (human prostate 1_L pA₂ of 9.2 with 25 fold selectivity over rat aorta 1_D) and sufficiently long elimination half-life in human volunteers (11-17 hour) for once a day administration.

Key words: active transport, drug design, drug discovery, drug disposition, hepatobiliary transport, pharmacokinetics, structure-activity relationships