sitagliptin and Epilepsy--Tonic-Clonic

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

Topics: Animals; Diabetes Mellitus, Type 2; Dogs; Epilepsy, Tonic-Clonic; Ether-A-Go-Go Potassium Channels; Female; Hypoglycemic Agents; Male; Mice, Inbred C57BL; Mice, Knockout; Oxadiazoles; Pyrimidines; Receptors, G-Protein-Coupled; Structure-Activity Relationship