Synthesis and Anticonvulsant Activity of Enaminone. 2. Further Structure-Activity Correlations.

Article abstract of DOI:10.1021/jm00066a003

This report continues the in-depth evaluation of methyl 4-<(p-chlorophenyl)amino>-6-methyl-2-oxocyclohex-3-en-1-oate, 1 (ADD 196022), and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 2, two potent anticonvulsant enaminones.These compounds were evaluated employing the amygdala kindling model.Neither 1 nor 2 was active against amygdala kindled seizures, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported.Additional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg.Several active analogs have been prepared with the view to minimizing toxicity.In a special ip rat screen developed by the Antiepileptic Drug Development (ADD) Program, these newer analogs were evaluated for protection against maximal electroshock seizures (MES) at 10 mg/kg and neurotoxicity at 100 mg/kg.From this screen, several compounds were shown to be safer alternatives, the most notable was methyl 4-<(p-bromophenyl)amino>-6-methyl-2-oxocyclohex-3-en-1-oate, 13.Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a protective index (TD50/ED50) of > 67.By variation in the ring size, additional aromatic substitutions and the synthesis of acyclic analogs, these newer compounds provide a more definitive insight into the structure-activity correlation.CLOGP evaluation and molecular modeling studies are also provided to further elaborate the molecular characteristics of potential anticonvulsant enaminones.