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J Med Chem. 2007 Feb 22;50(4):607-10. Epub 2007 Jan 23.

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

Author information

1
Chemistry Research and Development, Neuroscience, HTS/Molecular Pharmacology, Molecular Structure and Design, and Inflammation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ddamico@amgen.com

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 approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

PMID:
17243660
DOI:
10.1021/jm061224g
[Indexed for MEDLINE]

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