1. 3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation
- Author
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Tanya Peterkin, Kaustav Biswas, Neil G. Andersen, Babak Riahi, Jian J. Chen, Gondi N. Kumar, Janan Jona, Kevin Yang, Judy Wang, Derin C. D'amico, Jason Brooks Human, Benny C. Askew, Thomas T. Nguyen, Qingyian Liu, Augustus Kamassah, Margaret M. Faul, Nobuko Nishimura, Christopher H. Fotsch, Wenyuan Qian, Eileen Johnson, Jiawang Zhu, Toshihiro Aya, Nianhe Han, Randall W. Hungate, and John T. Colyer
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Bradykinin ,Pain ,Receptor, Bradykinin B1 ,Biochemistry ,Chemical synthesis ,Piperazines ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,Dogs ,Drug Discovery ,Acetamides ,Potency ,Animals ,Receptor ,Molecular Biology ,G protein-coupled receptor ,Sulfonyl ,chemistry.chemical_classification ,Inflammation ,Molecular Structure ,Organic Chemistry ,Stereoisomerism ,Rats ,Bradykinin B1 Receptor Antagonists ,chemistry ,Models, Animal ,Lactam ,Molecular Medicine ,Rabbits ,Acetamide - 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.
- Published
- 2011