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Aryl sulfonamides containing tetralin allylic amines as potent and selective bradykinin B1 receptor antagonists |
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| Authors: | Qingyian Liu Wenyuan Qian Aiwen Li Kaustav Biswas Jian Jeffrey Chen Christopher Fotsch Nianhe Han Chester Yuan Leyla Arik Gloria Biddlecome Eileen Johnson Gondi Kumar Dianna Lester-Zeiner Gordon Y. Ng Randall W. Hungate Benny C. Askew |
| Affiliation: | 1. Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;2. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;3. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;4. Department of Inflammation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States |
| Abstract: | The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC50 = 1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats. |
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