Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations.
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.
Scott
K R
KR
Department of Medicinal Chemistry, College of Pharmacy and Pharmacal Sciences, Howard University, Washington, D.C. 20059.
Edafiogho
I O
IO
Richardson
E L
EL
Farrar
V A
VA
Moore
J A
JA
Tietz
E I
EI
Hinko
C N
CN
Chang
H
H
el-Assadi
A
A
Nicholson
J M
JM
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
D000927:Anticonvulsants; D001596:Benzylamines; D003509:Cyclohexanecarboxylic Acids; D003514:Cyclohexylamines; C082302:ADD 196022; C082303:methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate