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3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation |
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| Authors: | Chen Jian Jeffrey Nguyen Thomas D'Amico Derin C Qian Wenyuan Human Jason Aya Toshihiro Biswas Kaustav Fotsch Christopher Han Nianhe Liu Qingyian Nishimura Nobuko Peterkin Tanya A N Yang Kevin Zhu Jiawang Riahi Babak Bobby Hungate Randall W Andersen Neil G Colyer John T Faul Margaret M Kamassah Augustus Wang Judy Jona Janan Kumar Gondi Johnson Eileen Askew Benny C |
| Affiliation: | a Department of Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States b Department of Process Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States c Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States d Department of Pharmaceutical Science, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States e Department of Pharmacokinetics & Drug Metabolism, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States f Department of Medicinal Chemistry, Serono Research Institute, Rockland, MA, United States |
| Abstract: | The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC50 of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described. |
| Keywords: | Bradykinin B1 Antagonist Pain Inflammation GPCR Oxopiperazine Tetralin |
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