title: Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy and Pharmacal Sciences, Howard University, Washington, D.C. 20059.
authors.forename: K R
authors.initials: KR
authors.lastname: Scott
authors.forename: I O
authors.initials: IO
authors.lastname: Edafiogho
authors.forename: E L
authors.initials: EL
authors.lastname: Richardson
authors.forename: V A
authors.initials: VA
authors.lastname: Farrar
authors.forename: J A
authors.initials: JA
authors.lastname: Moore
authors.forename: E I
authors.initials: EI
authors.lastname: Tietz
authors.forename: C N
authors.initials: CN
authors.lastname: Hinko
authors.forename: H
authors.initials: H
authors.lastname: Chang
authors.forename: A
authors.initials: A
authors.lastname: el-Assadi
authors.forename: J M
authors.initials: JM
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003514:Cyclohexylamines; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D001596:Benzylamines; D003509:Cyclohexanecarboxylic Acids; D003514:Cyclohexylamines; C082302:ADD 196022; C082303:methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate