Design, Synthesis And SAR Of Novel Peroxisome Proliferator-activated Receptor Agonists

Type 2 diabetes is a metabolic disease characterized by insulin resistance, hyperglycaemia, and hyperlipidemia, leading to impaired secretion of insulin in the later stsges. The disease is often associated with obesity, dyslipidemia, and hypertension , causing increased cardiovascular risks. Discovery of the insulin-sensitizing drugs thiazolidinedione(TZD) and the drug-target (Peroxisome proliferator-activated receptors, PPARs) offers a new route for the treatment of type 2 diabetes. PPARs are members of a huge nuclear hormone receptor superfamily, a group of nuclear proteins that mediate the specific effects of small lipophhilic compounds, such as steroids, retinoids, and fatty acids, on DNA transcription. Three subtypes of PPARs have been identified and cloned from mouse and human: PPARα, PPARγ, and PPARδ. To date three PPARγagonists Troglitazone, Rosiglitazone and Pioglitazone have been launched, which, however, provide minor protection against eventual cardiovascular risks that develop with type 2 diabetes. A new strategy of designing novel anti-diabetics is to combine the insulin sensitizing and glucose regulating activity of a PPARγagonists with lipid/cholesterol modulating properties of PPARαagonists (fibrate) into a single molecule. Dual-acting PPARαand PPARγagonists, designed to combine the beneficial effects seen with insulin sensitizers and fibrate, could be new drugs to 2 type diabetes.In order to find new and more effective drugs for the type 2 diatebes, the following work had been carried out in the thesis:1. Scrutinizing the structures of PPAR agonists and the binding feature of agonists to the receptors, a novel virtual library of PPAR agonists was constructed by structure-based drug design and combinatorial library method. Virtual screening was conducted by DOCKoperation, which automatically simulated the interaction between the ligands and receptors. Those strong-binding virtual compounds were selected according to the scoring functions. Six series of compounds composed of diverse building blocks were designed and synthesized in order to search for lead compounds with dual activity. X=H, NR₁=H, -C₂H₅R2=-CH₂OH, -CH₂COOHR3=-CH₃, -C₂H₅, -iC₃H₇, -C₅H₉, -C₆H₁₁, -C₆H_{5…}2. One hundred and forty-five chemical substances including ninety new compounds were prepared, of which eighty-five novel compounds are target molecules. All the targets moleculars were identified by ¹HNMR (300MHz) and MS (EI, FAB, or ESI), twenty-four of which were identified by high revolution mass spectroscopy. The compound FJ-07-17 was also identified by X-ray crystallography.3. Most of the target compounds were evaluated in vitro. Some of the compounds evaluated show strong binding affinities to PPARγ. Some of the compounds were found possessing approximate activity to Pioglitazone in vitro PPARαand PPARγtransactivation. The Structure-activity relationships of synthsized compounds and transactivation data offered detailed molecular information for design and synthesis of new compounds. The evaluation of compound FJ-08-46 in vivo is in progresss.4. Some compounds were in vitro tested for the activity on cell differentiation and proliferation. The compound FJ-05-05 was found to exhibit moderate inhibition of HT-29 cell line.