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Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles |
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| Authors: | McAtee John J Dodson Jason W Dowdell Sarah E Erhard Karl Girard Gerald R Goodman Krista B Hilfiker Mark A Jin Jian Sehon Clark A Sha Deyou Shi Dongchuan Wang Feng Wang Gren Z Wang Ning Wang Yonghui Viet Andrew Q Yuan Catherine C K Zhang Daohua Aiyar Nambi V Behm David J Carballo Luz H Evans Christopher A Fries Harvey E Nagilla Rakesh Roethke Theresa J Xu Xiaoping Douglas Stephen A Neeb Michael J |
| Affiliation: | Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com |
| Abstract: | Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored. |
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