Abstract
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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.015180.
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ABBREVIATIONS: BPH, benign prostatic hyperplasia; AUC0-T, area under the plasma concentration-time curve; CL′int, intrinsic clearance; clogP, calculated log P; Cmax, maximum concentration; fu, fraction unbound; HPLC, high performance liquid chromatography; IPRL, isolated perfused rat liver; kel, terminal elimination rate constant; log D7.4, log of octanol/water partition coefficient at pH 7.4; LC-MS/MS, liquid chromatographytandem mass spectrometry; 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; UK-191,005, (3,4-dihydroxy-pyrrolidin-1-yl)-{4-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxyquinazolin-2-yl]-[1,4]diazepan-1-yl}-methanone; UK-294,315, {4-[4-amino-5-(4-fluoro-phenyl)-6,7-dimethoxy-quinolin-2-yl]-[1,4]diazepan-1-yl}-morpholin-4-yl-methanone; t1/2, terminal elimination half-life; Tmax, time to maximum concentration.
- Received February 14, 2007.
- Accepted May 11, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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