Discovery and anticonvulsant activity of the potent metabolic inhibitor 4-amino-N-(2,6-dimethylphenyl)-3,5-dimethylbenzamide.
Compound 2 [4-amino-N-(2,6-dimethylphenyl)benzamide] is an effective anticonvulsant in several animal models. For example, following oral administration to mice, it antagonized maximal electroshock (MES) induced seizures with an ED50 of 1.7 mg/kg. During drug disposition studies with 2, we found that it was rapidly metabolized by N-acetylation. Thirty minutes after oral administration of 1.7 mg/kg of 2 to mice, plasma concentrations of parent drug and the N-acetyl metabolite 5 were 1.09 and 0.41 microgram/mL, respectively. Six hours postadministration the concentrations were 0.23 and 0.22 microgram/mL, respectively. In order to sterically preclude or diminish the rate of metabolic N-acetylation, we synthesized analogues of 2 possessing either one (3) or two (4) methyl groups ortho to the 4-amino substituent. Both compounds antagonized MES-induced seizures after administration to mice; oral ED50 values for 3 and 4 were 3.5 and 5.6 mg/kg, respectively. Compound 3 was rapidly metabolized by N-acetylation. However, 4 provided exceptionally high and long-lived plasma concentrations of parent drug; no N-acetyl metabolite could be detected. While 2 and 3 had no pharmacologically relevant effects on hexobarbital-induced sleeping time in mice, 4 was a potent, dose-dependent potentiator of sleeping time. Oral administration of 375 micrograms/kg led to a 61% increase in sleeping time relative to control values. Thus, 4 represents one of the most potent potentiators of hexobarbital-induced sleeping time described to date.
Robertson
D W
DW
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
Leander
J D
JD
Lawson
R
R
Beedle
E E
EE
Clark
C R
CR
Potts
B D
BD
Parli
C J
CJ
D000107:Acetylation; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006591:Hexobarbital / Q000494:pharmacology; D051379:Mice; D012640:Seizures / Q000188:drug therapy; D012890:Sleep / Q000187:drug effects
D000927:Anticonvulsants; D001549:Benzamides; C053811:LY 201409; D006591:Hexobarbital