Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity

Derin C. D'Amico, Toshi Aya, Jason Human, Christopher Fotsch, Jian Jeffrey Chen, Kaustav Biswas, Bobby Riahi, Mark H. Norman, Christopher A. Willoughby, Randall Hungate, Paul J. Reider, Gloria Biddlecome, Dianna Lester-Zeiner, Carlo Van Staden, Eileen Johnson, Augustus Kamassah, Leyla Arik, Judy Wang, Vellarkad N. Viswanadhan, Robert D. GronebergJames Zhan, Hideo Suzuki, Andras Toro, David A. Mareska, David E. Clarke, Darren M. Harvey, Laurence E. Burgess, Ellen R. Laird, Benny Askew, Gordon Ng

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed ∼30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

Original languageEnglish (US)
Pages (from-to)607-610
Number of pages4
JournalJournal of Medicinal Chemistry
Volume50
Issue number4
DOIs
StatePublished - Feb 22 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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