Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity.
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.
D'Amico
Derin C
DC
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
Aya
Toshi
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Human
Jason
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Fotsch
Christopher
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Chen
Jian Jeffrey
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Biswas
Kaustav
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Riahi
Bobby
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Norman
Mark H
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Willoughby
Christopher A
CA
Hungate
Randall
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Reider
Paul J
PJ
Biddlecome
Gloria
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Lester-Zeiner
Dianna
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Staden
Carlo Van
CV
Johnson
Eileen
E
Kamassah
Augustus
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Arik
Leyla
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Wang
Judy
J
Viswanadhan
Vellarkad N
VN
Groneberg
Robert D
RD
Zhan
James
J
Suzuki
Hideo
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Toro
Andras
A
Mareska
David A
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Clarke
David E
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Harvey
Darren M
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Burgess
Laurence E
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Laird
Ellen R
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Askew
Benny
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Ng
Gordon
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects; D002522:Chlorocebus aethiops; D002839:Chromans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D019277:Entropy; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D010998:Pleurisy / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065169:Bradykinin B1 Receptor Antagonists; D002839:Chromans