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Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines.
Jimonet, P; Audiau, F; Barreau, M; Blanchard, J C; Boireau, A; Bour, Y; Coléno, M A; Doble, A; Doerflinger, G; Huu, C D; Donat, M H; Duchesne, J M; Ganil, P; Guérémy, C; Honor, E; Just, B; Kerphirique, R; Gontier, S; Hubert, P; Laduron, P M; Le Blevec, J; Meunier, M; Miquet, J M; Nemecek, C; Mignani, S.
Afiliación
  • Jimonet P; Rhône-Poulenc S.A., Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesde, B.P. 14, F 94403 Vitry-sur-Seine Cedex, France.
J Med Chem ; 42(15): 2828-43, 1999 Jul 29.
Article en En | MEDLINE | ID: mdl-10425092
Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfóxidos / Tiazoles / Fármacos Neuroprotectores / Antagonistas de Aminoácidos Excitadores / Riluzol / Iminas Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 1999 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfóxidos / Tiazoles / Fármacos Neuroprotectores / Antagonistas de Aminoácidos Excitadores / Riluzol / Iminas Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 1999 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos