Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing thiazolidinediones

A series of substituted pyridyl- and quinolinyl-containing 2,4-thiazolidine diones having interesting cyclic amine as a linker have been synthesized. B oth unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypoli pidemic effects and compared with BRL compound 11 and BRL-49653, respective ly. Some of the potent compounds were converted to various salts in order t o obtain improved activities. Among all the salts evaluated, the maleate sa lt of unsaturated TZD 5a was found to be a very potent euglycemic and hypol ipidemic compound. Some of the more interesting compounds have also been ev aluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL- 49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor bi nding studies of PPAR gamma by 5a/5a maleate did not show any significant t ransactivation of PPAR alpha or PPAR gamma.