Design, Synthesis And Bioassay Of PPAR Agonists And LXRα Agonists

Peroxisome Proliferators-Activated Receptor (PPAR) is considered as a new target of antidiabetic drugs. In part I of this dissertation: (1) The hydrophobic fragments of thiazolindiones (TZDs) antidiabetic drugs were combined with the hydrophilic fragments from virtual screening, 16 of AT-substituted-carbamo-yl alkanoic acids and AT-substituted-acylamino benzoic acids(Al-A16) were designed and synthesized. A2, A3, A5, A7, A9-A13 and A16 at 10μM, showed limited activation of PPAR. (2) Based on the leader compound DC041060, we designed and synthesized 9 double carboxyl group compounds (B1-B9). The pharmacological test results showed that B4 and B7 showed PPARα,γ, 8 activity, B6 showed PPARγ/δdual activity, B9 showed PPARαactivity.LXRαand LXRβreceptors not only regulate cholesterol homeostasis, but also prevent the development of atherosclerosis. So discovering LXRs agonists, especially LXRα-slective agonists is very important. In part II of this dissertation, we employed the approach of Computer-Aided Drug Design (CADD), designed and synthesized 30 compounds (C1-C30). C13,C21,C22,C27 and C28 showed strong LXRαactivity.55 new compounds were designed, synthesized and screened as candidates of PPAR agonists or LXRαagonists, the chemical structure of these compounds have been characterized by the application of MS and ~1H-NMR spectra. The SAR of compounds was also summarized.