Design And Synthesis Of Novel PPARδ Agonists

In this thesis, the design and synthesis of a new type of PPARδagonist, derivatives of 2-(4-(2-(substituted benzylthio)thiazol-4-yl)phenoxy)acetic acid, were studied.The distribution and structural feature of PPARδwere introduced and the development of PPARδactivators and physical functions were described in detail. The structure-activity relationships (SAR) of phenoxy acetic acid drugs was summarized and the main pharmacophores were identified. Taking GW501516 as lead compound, preserving the two necessary pharmacophores 1,3-thiazole and phenoxy acid groups, some modifications were made at the 2 positions of the two groups respectively. Then two series of twenty-four new 2-(4-(2-(substitutedbenzylthio) thiazol-4-yl)phenoxy) acetic acid derivatives which had not been reported in literatures were designed and synthesized.In the base of the preparation methods of thiazole, the synthetic route of target compounds was designed and several reaction steps were optimized and improved. Using 4’-hydroxy-acetophenone as starting material, the target compounds were synthesized through six steps of reactions, including substitution, bromo-substitution, cyclization, etherification, hydrolysis and acidification. The structures of the target compounds were confirmed by MS and ~1H-NMR.The pharmacological evaluation of these target compounds is undergoing.