Synthesis and pharmacological activity of triazolo[1,5-a]triazine derivatives inhibiting eosinophilia.
In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino-1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives. We evaluated their inhibitory activity on the airway eosinophilia model, which was induced by the intravenous (iv) injection of Sephadex particles. In the 1,2,4-triazole series with various substituents at the 3 position of the triazole ring such as 2-furyl, pyridyl, and phenoxy, none of derivatives had comparable activity to the previously reported compound GCC-AP0341, 5-amino-3-(4-chlorophenyl)-1-[(methylamino)thiocarbonyl]-1H-1,2, 4-triazole. In the triazolo[1,5-a]triazine series, 2-(4-chlorophenyl)-6-methyl-1,2,4-triazolo[1,5-a]-1,3, 5-triazine-7(6H)-thione (3h) was highly potent, and when given orally it had an ID50 value of 0.3 mg/kg, which is comparable to that of GCC-AP0341. The fact that the structure-activity relationship of these two series was quite similar suggests that a common substructure, such as the 1,2,4-triazole ring with a substituted phenyl ring at the 3 position and a thiocarbonyl moiety at the 1 position, could contribute to the activity. Our selected compound 3h was less active than GCC-AP0341 in the antigen-induced hyper-responsiveness model in guinea pigs; however, we plan to carry out further studies on eosinophil functions, especially on their activation, using our two compounds, 3h and GCC-AP0341.
Pharmaceutical Research Division, Yoshitomi Pharmaceutical Industries, Ltd., 2-25-1, Shodai-Ohtani, Hirakata, Osaka 573-1153, Japan.
F
F
Akahoshi
S
S
Takeda
T
T
Okada
M
M
Kajii
H
H
Nishimura
M
M
Sugiura
Y
Y
Inoue
C
C
Fukaya
Y
Y
Naito
T
T
Imagawa
N
N
Nakamura
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000947:Antigens, Helminth / Q000276:immunology; D001200:Ascaris / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D002452:Cell Count / Q000187:drug effects; D003911:Dextrans / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C113640:2-(4-chlorophenyl)-6-methyl-1,2,4-triazolo(1,5-a)-1,3,5-triazine-7(6H)-thione; D018927:Anti-Asthmatic Agents; D000947:Antigens, Helminth; D003911:Dextrans; C100738:GCC-AP 0341; D014227:Triazines; D014230:Triazoles; C025614:sephadex