Development of potent and selective small-molecule human Urotensin-II antagonists |
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Authors: | McAtee John J Dodson Jason W Dowdell Sarah E Girard Gerald R Goodman Krista B Hilfiker Mark A Sehon Clark A Sha Deyou Wang Gren Z Wang Ning Viet Andrew Q Zhang Daohua Aiyar Nambi V Behm David J Carballo Luz H Evans Christopher A Fries Harvey E Nagilla Rakesh Roethke Theresa J Xu Xiaoping Yuan Catherine C K Douglas Stephen A Neeb Michael J |
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Institution: | Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com |
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Abstract: | This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities. |
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