Abstract
This dissertation is concerned with the discovery of novel PPAR□ agonists for oral antidiabetic therapy through SBDD (Structure Based Drug Design).The work is divided into two parts: the first part is the development of a series of novel indole-based analogs including structure based design, chemosynthesis and structural biology and structure-activity relationship (SAR), the second part is a series of quinoline-based analogs including drug design, chemosynthesis, structural biology and structure-activity relationship.In the first part, a series of novel indole-based PPARs agonists is described leading to the discovery of compound 65, a highly potent PPAR pan agonist. The tail part of 54 makes extensive hydrophobic interaction with the PPAR□ protein resulting in potent activity. The compound 65 was modified to compound 74, which showed potent PPAR□□agonist activity and compound 76 showed potent PPAR□□□□□activity. Structure biology analysis of indole-based PPAR agonists 65、74、76 in complex with PPAR□ protein was carried out to explain the structure-activity relationships and provides structural insight. At the same time, after performing a systematic SAR study, napthphenone tail part 54 was replaced with phenyl-benzophenone 141c, which resulted in PPAR□ selective compound 112. In the indole series, potent PPAR□□□□□、PPAR □□□□and PPAR□□agonists were developed successfully.In the second part, quinoline-based analogs were synthesized as ring expansion replacement of indole based analogs. PPAR□□□ agonist 165 with tail part showed dual agonist activity, while replacement of naphthophenone hydrophobic tail part with phenyl-benzophenone in 167 displayed the most potent PPAR□ activity with an IC50/EC50 value of 50/ 50 nM in PPAR□. In the quinoline series, potent PPAR□□□ and PPAR□□agonists were developed successfully.This dissertation describes rational drug design, chemosynthesis and structural biology studies of indole and quinoline series of compounds as PPARs agonist which resulted in identification of potent selective and non-selective PPAR agonist for the treatment of diabetes.