title: Synthesis and pharmacological activity of triazole derivatives inhibiting eosinophilia.
abstract: In order to develop novel antiasthmatic agents based on a new mechanism of action, a series of 3-substituted 5-amino-1-[(methylamino)(thiocarbonyl)]-1H-1,2,4-triazole derivatives were synthesized and evaluated in a model in which eosinophilia was induced in the airway through intravenous (iv) injection of Sephadex particles on days 0, 2, and 5. After screening of several hundred derivatives, we finally identified the highly potent eosinophilia inhibitor 5-amino-3-(4-chlorophenyl)-1-[(methylamino)(thiocarbonyl)]-1H-tria zole (23c, GCC-AP0341), which had ID50 values of 0.3 and 0.07 mg/kg when administered orally (os) and intraperitoneally (ip), respectively. This compound showed complete inhibition of the hypersensitivity induced by ascaris inhalation at an ip dose of 1 mg/kg as well as low toxicity, with an LD50 value of > 2.0 g/kg in mice. Extensive study of its mechanism of action revealed that 23c inhibited eosinophil survival induced by interleukin-5 (IL-5), but had little or no effect on leukotriene D4 (LTD4) or platelet-activating factor (PAF)-induced responses. Taken together, these results suggest 23c as a novel candidate for the treatment of chronic asthma. Further studies are now underway.
authors.affiliation: Research Division, Green Cross Corporation, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Naito
authors.forename: F
authors.initials: F
authors.lastname: Akahoshi
authors.forename: S
authors.initials: S
authors.lastname: Takeda
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Kajii
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: M
authors.initials: M
authors.lastname: Sugiura
authors.forename: C
authors.initials: C
authors.lastname: Fukaya
authors.forename: Y
authors.initials: Y
authors.lastname: Kagitani
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000947:Antigens, Helminth / Q000276:immunology; D001200:Ascaris / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D003911:Dextrans; D004802:Eosinophilia / Q000188:drug therapy*; D004804:Eosinophils / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018927:Anti-Asthmatic Agents; D000947:Antigens, Helminth; D003911:Dextrans; C100738:GCC-AP 0341; D015848:Interleukin-5; D011994:Recombinant Proteins; D014230:Triazoles; D003907:Dexamethasone; C025614:sephadex