MEDI 251 |
| The therapeutic utility of insulin secretagogues in aiding type II diabetics to maintain glucose homeostasis is well established. However, hypoglycemia is a common side effect with many current insulin secretagogues. Fatty acids have been shown to be promoters of glucose stimulated insulin secretion (GSIS), and a therapeutic agent working through the same pathway potentially could avoid undesirable hypoglycemia. The identification of fatty acids as the ligands for the previously orphaned receptor GPR40 has sparked interest in GPR40 modulators as potential therapeutically useful potentiators of GSIS. We identified certain β-substituted carboxylic acids as moderately potent GPR40 agonists. Modification of the substituents on the carboxylic acid β-position and the benzyl ether resulted in compounds displaying improved potency and pharmacokinetic profile. The synthesis, optimization, and evaluation of the effects on GSIS in rodents by β-substituted carboxylic acids will be described.
|
|
Hot Topics in Medicinal Chemistry
1:30 PM-4:00 PM, Wednesday, August 22, 2007 BCEC -- 210 B/C, Oral
Division of Medicinal Chemistry |
