title: Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity.
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.
authors.affiliation: 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
authors.forename: Derin C
authors.initials: DC
authors.lastname: D'Amico
authors.forename: Toshi
authors.initials: T
authors.lastname: Aya
authors.forename: Jason
authors.initials: J
authors.lastname: Human
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.forename: Kaustav
authors.initials: K
authors.lastname: Biswas
authors.forename: Bobby
authors.initials: B
authors.lastname: Riahi
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Willoughby
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Reider
authors.forename: Gloria
authors.initials: G
authors.lastname: Biddlecome
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.forename: Carlo Van
authors.initials: CV
authors.lastname: Staden
authors.forename: Eileen
authors.initials: E
authors.lastname: Johnson
authors.forename: Augustus
authors.initials: A
authors.lastname: Kamassah
authors.forename: Leyla
authors.initials: L
authors.lastname: Arik
authors.forename: Judy
authors.initials: J
authors.lastname: Wang
authors.forename: Vellarkad N
authors.initials: VN
authors.lastname: Viswanadhan
authors.forename: Robert D
authors.initials: RD
authors.lastname: Groneberg
authors.forename: James
authors.initials: J
authors.lastname: Zhan
authors.forename: Hideo
authors.initials: H
authors.lastname: Suzuki
authors.forename: Andras
authors.initials: A
authors.lastname: Toro
authors.forename: David A
authors.initials: DA
authors.lastname: Mareska
authors.forename: David E
authors.initials: DE
authors.lastname: Clarke
authors.forename: Darren M
authors.initials: DM
authors.lastname: Harvey
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Burgess
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Benny
authors.initials: B
authors.lastname: Askew
authors.forename: Gordon
authors.initials: G
authors.lastname: Ng
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065169:Bradykinin B1 Receptor Antagonists; D002839:Chromans