- Synthesis and pharmacological activity of triazole derivatives inhibiting eosinophilia
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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-triazole (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.
- Naito, Youichiro,Akahoshi, Fumihiko,Takeda, Shinji,Okada, Takehiro,Kajii, Masahiko,Nishimura, Hiroko,Sugiura, Masanori,Fukaya, Chikara,Kagitani, Yoshio
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p. 3019 - 3029
(2007/10/03)
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- HETEROCYCLIC NITRO COMPOUNDS. 25. 1-HYDROXYMETHYL-3-NITRO-1,2,4-TRIAZOLES AND THEIR DERIVATIVES
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1-Hydroxymethyl derivatives of tetrazoles were obtained by the reaction of 1,2,4-triazole and 3-nitro-5-substituted triazoles with formaldehyde in water.The hydroxy groups were replaced by chlorine, and the hydroxymethyltriazoles were acetylated and tosylated.The chloro and tosyl groups are readily replaced by iodine by the action of potassium and ammonium iodide in acetone.
- Pevzner, M. S.,Ivanov, P. A.,Gladkova, N. V.,Sushchenko, O.N.,Tverdokhlebov, V. P.,Myasnikova, Z. S.
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p. 189 - 194
(2007/10/02)
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