title: Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344.
abstract: To investigate the pathophysiological role of bradykinin and to develop a drug for inflammatory diseases, we discovered an orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344, N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2, 4dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethyl aminocarbonyl) cinnamylamide hydrochloride. This compound competitively displaced [3H]bradykinin binding to bradykinin B2 receptors present in guinea-pig ileum membrane with an IC50 value of 6.6 X 10(-10) M. In isolated guinea-pig ileum preparations, it also antagonized bradykinin-induced contraction with a pA2 value of 9.3. In human lung fibroblast IMR-90 cells, FR167344 displaced [3H]bradykinin binding to human bradykinin B2 receptors with an IC50 value of 1.3 X 10(-8) M, but not [3H]des-Arg10-kallidin binding to human bradykinin B1 receptors. In vivo, oral administration of FR167344 inhibited bradykinin-induced bronchoconstriction in guinea pigs and the bradykinin-induced hypotensive response for 6 h in rats. These results show that FR167344 is a potent, selective, orally active and long acting bradykinin B2 receptor antagonist.
authors.affiliation: Department of Pharmacology, Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Inamura
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: C
authors.initials: C
authors.lastname: Hatori
authors.forename: H
authors.initials: H
authors.lastname: Sawai
authors.forename: J
authors.initials: J
authors.lastname: Hirosumi
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: H
authors.initials: H
authors.lastname: Kayakiri
authors.forename: S
authors.initials: S
authors.lastname: Satoh
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Oku
authors.forename: K
authors.initials: K
authors.lastname: Nakahara
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D005260:Female; D005347:Fibroblasts; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism
chemical_list: D065168:Bradykinin Receptor Antagonists; C106745:FR 167344; D011725:Pyridines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D001920:Bradykinin