3-Phenoxypyridine 1-oxides as anticonvulsant agents.
The anticonvulsant activity of a series of 3-phenoxypyridine 1-oxides is described. An investigation carried out to optimize the activity/side effect ratio provided 4-methyl-3-phenoxypyridine 1-oxide, 3, as the derivative of choice. Overall, 3 has a pharmacological profile that is very similar to phenytoin. It exhibited significant anticonvulsant activity at doses that did not produce ataxia or sedation but caused increased spontaneous behavioral activity not seen with most anticonvulsants. The short duration of pharmacological effect of 3 was attributed to metabolic hydroxylation at the C-4 pyridine methyl group; however, structural modifications designed to inhibit this metabolic pathway were unsuccessful.
Pavia
M R
MR
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48104.
Taylor
C P
CP
Hershenson
F M
FM
Lobbestael
S J
SJ
Butler
D E
DE
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D006900:Hydroxylation; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors
D000927:Anticonvulsants; D003497:Cyclic N-Oxides; D011725:Pyridines