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.

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]-4H-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-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-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).

Synthesis, structure-activity relationships, and anticonvulsant activities of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives as orally active AMPA receptor antagonists.

As part of a program aimed at discovering orally active 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonists, we screened our compound library and identified 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (7) as a lead compound that inhibited kainate-induced neurotoxicity mediated by AMPA receptors in rat hippocampal cultures. Structure-activity relationship studies of a series of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives revealed that substituents on the phenyl ring attached to the 2-amino group and the 4H-pyrido[3,2-e][1,3]thiazin-4-one ring system play an important role in inhibitory activity against kainate-induced neurotoxicity. Several analogs bearing a phenyl group with a 4-substituent or five- or six-membered ring fused at the 3,4-positions exhibited potent inhibitory activity against kainate-induced neurotoxicity. Further, some of these compounds exhibited significant suppression of maximal electroshock seizure in mice following oral administration. Of these compounds, 2-[(4-chlorophenyl)(methyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (16i) (YM928) demonstrated the most potent inhibitory effect with an ED50 value of 7.4mg/kg.

The synthesis and structure-activity relationship of substituted N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors.

It is believed that beta-amyloid aggregation is an important event in the development of Alzheimer's disease. In the course of our studies to identify beta-amyloid aggregation inhibitors, a series of N-phenyl anthranilic acid analogs were synthesized and studied for beta-amyloid inhibition activity. The synthesis, structure-activity relationship, and in vivo activity of these analogs are discussed.