QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.015180v1 35/8/1435    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Betts, A. Articles by Morgan, P. Search for Related Content PubMed PubMed Citation Articles by Betts, A. Articles by Morgan, P.

Impact of Physicochemical and Structural Properties on the Pharmacokinetics of a Series of 1_L-Adrenoceptor Antagonists

Pfizer Global Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism (A.B., F.A., I.G., R.W., K.B., P.M.) and Department of Discovery Chemistry (D.F.), Sandwich, Kent, United Kingdom

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 pA₂ 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.

This article has been cited by other articles:

				A. Collett, R. H. Stephens, M. D. Harwood, M. Humphrey, L. Dallman, J. Bennett, J. Davis, G. L. Carlson, and G. Warhurst Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the {alpha}-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption Drug Metab. Dispos., January 1, 2008; 36(1): 87 - 94. [Abstract] [Full Text] [PDF]