标题：Synthesis and Pharmacological Evaluation of 3-[(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)(phenyl)amino]propanenitrile Derivatives as Orally Active AMPA Receptor Antagonists
摘要：In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4 H -pyrido[3,2- e ][1,3]thiazin-4-one ( 4 ) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4 H -pyrido[3,2- e ][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile ( 25 ) and 3-[(2,2-difluoro-2 H -1,3-benzodioxol-5-yl)(4-oxo-4 H -pyrido[3,2- e ][1,3]thiazin-2-yl)amino]propanenitrile ( 27 ) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 ( 5 ) and talampanel ( 1 ).
