3-Phenoxypyridine 1-oxides as anticonvulsant agents

• Published in: Journal of medicinal chemistry 1988-04, Vol.31 (4), p.841-847
• Main Authors: Pavia, Michael R, Taylor, Charles P, Hershenson, Fred M, Lobbestael, Sandra J, Butler, Donald E
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - pharmacology; Chemistry; Conditioning, Operant - drug effects; Cyclic N-Oxides - chemical synthesis; Cyclic N-Oxides - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hydroxylation; Male; Mice; Motor Activity - drug effects; Organic chemistry; Preparations and properties; Pyridines - chemical synthesis; Pyridines - pharmacology; Structure-Activity Relationship; Time Factors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00399a027

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.