Effect of FK3657, a non-peptide bradykinin B2 receptor antagonist, on allergic airway disease models.
Bradykinin has been suggested to be involved in allergic diseases. In this study, we tested the effect of FK3657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)-oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide), an orally active non-peptide bradykinin B(2) receptor antagonist, on allergic airway disease models in guinea pigs. FK3657 given orally inhibited bradykinin-induced or dextran sulfate (an activator of kinin-kallikrein cascade)-induced bronchoconstriction and plasma extravasation in the lower airways (trachea and main bronchi) and nasal mucosa of guinea pigs with ED(50) of 0.04-0.23 mg/kg. In the antigen-induced dual asthmatic response model of guinea pigs, FK3657 significantly attenuated the late phase asthmatic response, but not the immediate asthmatic response. FK3657 also significantly inhibited the 2,4-tolylene diisocyanate (TDI)-induced plasma extravasation in nasal mucosa of TDI-sensitized guinea pigs. These results suggest that oral FK3657 may be useful for asthma or allergic rhinitis as a therapeutic drug.
Hirayama
Yoshitaka
Y
Department of Immunology and Inflammation, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan. yoshitaka_hirayama@po.fujisawa.co.jp
Miyayasu
Kikuo
K
Yamagami
Kaoru
K
Imai
Takumi
T
Ohkubo
Yoshitaka
Y
Mutoh
Seitaro
S
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000473:pathology; D001920:Bradykinin; D065094:Bradykinin B2 Receptor Antagonists; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents; D002199:Capillary Permeability / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D009297:Nasal Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D010047:Ovalbumin; D010949:Plasma / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D014051:Toluene 2,4-Diisocyanate; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D065094:Bradykinin B2 Receptor Antagonists; D016085:Bronchoconstrictor Agents; C105311:FR 173657; D011804:Quinolines; D014051:Toluene 2,4-Diisocyanate; D010047:Ovalbumin; D001920:Bradykinin