benzyl>-2,4-thiazolidinediones as Potent Antihyperglycemic Agents

Article abstract of DOI:10.1021/jm00049a017

A series of <(ureidoethoxy)benzyl>-2,4-thiazolidinediones and <<(heterocyclylamino)alkoxy>benzyl>-2,4-thiazolidinediones was synthesized from the corresponding aldehydes.Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045).The benzoxazole 49, a cyclic analogue of 16, was a very potent enhancer of insulin sensitivity, and by modification of the aromatic heterocycle, an aminopyridine, 37, was identified as a lead compound from SAR studies.Evaluation of antihyperglycemic activity together with effects on blood hemoglobin content, to determine the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 BI/6 ob/ob mice.From these studies, BRL 49653 (37) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against reductions in blood hemoglobin content, for further evaluation.