Synthesis and anticonvulsant activity of enaminones. Part 7. Synthesis and anticonvulsant evaluation of ethyl 4-[(substituted phenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylates and their corresponding 5-methylcyclohex-2-enone derivatives.
Further investigation of the potential anticonvulsant activity of the enaminones was attempted to discern the possible role of metabolites as the active/co-active entities of the esters of the enaminones. A series of 5-methyl-2-cyclohexene enaminones, the hypothesised metabolites corresponding to a sequence of active and inactive esters were synthesised and evaluated for anticonvulsant activity. With two exceptions, ethyl 4-[(4-cyanophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1k), and 3-[N-(4-cyanophenyl)amino]-5-methyl-2-cyclohexenone (3g), and ethyl 4-(phenylamino)-6-methyl-2-cyclohexenone (1n), and 3-N-(phenylamino)-5-methyl-2-cyclohexenone (3j), anticonvulsant screening data were parallel, with the ester and their putative decarboxylated analogue displaying similar activity. The most active analogue evaluated in this series, ethyl 4-[(4-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1e), which displayed an ED(50) of 16.7 mg kg(-1) and a TD(50) of 110.7 mg kg(-1) (protective index, PI = TD(50)/ED(50) = 6.6) in the maximal electroshock seizure (MES) test in mice and an ED(50) of 3.0 mg kg(-1) and a TD(50) >250 mg kg(-1) (PI > 83.3) in rats in the same evaluation, making this compound the most potent enaminone emanating from our laboratories. Pharmacokinetic evaluation of compound 1e in rats using LC/MS analysis unequivocally provides evidence that this compound is converted into the decarboxylated analogue 3a in the brain and the urine.
Eddington
Natalie D
ND
Department of Pharmaceutical Sciences, Pharmacokinetics Biopharmaceutics Laboratory, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD 21201-4403, USA.
Cox
Donna S
DS
Khurana
Manoj
M
Salama
Noha N
NN
Stables
James P
JP
Harrison
Sylvia J
SJ
Negussie
Abraham
A
Taylor
Robert S
RS
Tran
Uy Q
UQ
Moore
Jacqueline A
JA
Barrow
Judith C
JC
Scott
K R
KR
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001923:Brain Chemistry; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004597:Electroshock; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D015222:Sodium Channels / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D003512:Cyclohexanones; D015222:Sodium Channels