3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation.

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 EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.

• Authors: Jian Jeffrey Chen, Thomas Nguyen, Derin C D'Amico, Wenyuan Qian, Jason Human, Toshihiro Aya, Kaustav Biswas, Christopher Fotsch, Nianhe Han, Qingyian Liu, Nobuko Nishimura, Tanya A N Peterkin, Kevin Yang, Jiawang Zhu, Babak Bobby Riahi, Randall W Hungate, Neil G Andersen, John T Colyer, Margaret M Faul, Augustus Kamassah, Judy Wang, Janan Jona, Gondi Kumar, Eileen Johnson, Benny C Askew
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 11 Pg. 3384-9 (Jun 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21514825 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Acetamides
• Bradykinin B1 Receptor Antagonists
• Piperazines
• Receptor, Bradykinin B1

Topics

• Acetamides (chemical synthesis, chemistry, therapeutic use)
• Animals
• Bradykinin B1 Receptor Antagonists
• Dogs
• Inflammation (drug therapy)
• Inhibitory Concentration 50
• Mice
• Models, Animal
• Molecular Structure
• Pain (drug therapy)
• Piperazines (chemical synthesis, chemistry, therapeutic use)
• Rabbits
• Rats
• Receptor, Bradykinin B1 (chemistry)
• Stereoisomerism
• Structure-Activity Relationship