Development of antidiabetic agents targeting PPARγ

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We have reported that we designed docosahexaenoic acid (DHA) derivatives as PPARγ ligands based on the x-ray crystal structure of the ligand binding domain of PPARγ, and synthesized them from DHA. Furthermore, we found one of them, 4-OH derivative, has significant potency for PPARγ transactivation. In addition to 4-OH group, a conjugate diene structure around C(5)-position was found to be important for the transactivation indicating conformationally restricted analogs might show more potent activity. Thus, we designed new hybrid compounds composed of a head group of cinnamic acid and a tail group from polyunsaturated fatty acid. Side chain part of polyunsaturated fatty acid as a tail group was derived from eicosapentaenoic acid by iodolactonization, hydrolysis, glycol-cleavage, reduction and then bromination. Cinnamic acid derivative as a head group and the side chain bromide of polyunsaturated fatty acid as a tail group were bonded by Williamson ether production method or Mitsunobu reaction. Thus, we synthesized more than twenty new compounds. PPAR transactivation potency of these synthesized compounds was evaluated by the luciferase assay method. We found that PPARγ transactivation potencies of all compounds are weak while some of them significantly transactivate PPARα which is a subtype of PPARγ.