title: Impact of physicochemical and structural properties on the pharmacokinetics of a series of alpha1L-adrenoceptor antagonists.
abstract: A rational drug discovery process was initiated to design a potent and prostate-selective alpha1(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 alpha1(L) pA(2) of 9.2 with 25-fold selectivity over rat aorta alpha1(D)) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration.
authors.affiliation: Pfizer Global Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Sandwich, Kent, United Kingdom. alison.betts@pfizer.com
authors.forename: Alison
authors.initials: A
authors.lastname: Betts
authors.forename: Fidelma
authors.initials: F
authors.lastname: Atkinson
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: David
authors.initials: D
authors.lastname: Fox
authors.forename: Rob
authors.initials: R
authors.lastname: Webster
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
mesh_terms: D000293:Adolescent; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000328:Adult; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D018592:Cross-Over Studies; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D015394:Molecular Structure; D011485:Protein Binding; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016037:Single-Blind Method; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C483030:4-amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-(4-(morpholinocarbonyl)--perhydro-1,4-diazepin-1-yl)quinoline; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001381:Azepines; D001798:Blood Proteins; D007546:Isoquinolines; C523956:N-(2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl)-methanesulfonamide; D011799:Quinazolines; D011804:Quinolines; D013449:Sulfonamides