Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists |
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| Affiliation: | 1. Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea;2. Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea;1. Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK;2. Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;3. Neuroscience Discovery, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;4. Musculoskeletal Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA |
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| Abstract: | The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13 nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability. |
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| Keywords: | Urotensin-II receptor Antagonists Cardiovascular disease |
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