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

Type II diabetes is a complex, metabolic disorder characterized by hyperglycemia and subsequent chronic complications leading to renal failure, blindness and coronary artery disease. Hyperglycemia in type II diabetes is caused by increased insulin resistance and impaired insulin secretion from the pancreas. The discovery of the insulin-sensitizing drugs thiazolidinediones (TZDs) and validation of the drug-target (Peroxisome proliferator-activated receptors, PPARs) offers a novel approach for the treatment of type II diabetes. PPARs are members of a super family of nuclear receptors that include steroid, retinoid, and thyroid hormone receptors. Three subtypes of PPARs, PPARα, PPARγ, and PPARδ, have been identified and cloned from mouse and human. To date, three PPARγ agonists, Troglitazone, Rosiglitazone and Pioglitazone have been launched, Unfortunately, these PPARγ agonists provide minor protection against cardiovascular risks associated with type II diabetes. A new strategy of designing novel anti-diabetics is to incorporate the insulin sensitizing and glucose regulating activities of PPARy agonists with lipid/cholesterol modulating properties of PPARa agonists (fibrate) into a single molecule. Dual-functioned PPARα and PPARγ agonists could, take advantage of the beneficial effects of both insulin sensitizers and fibrate, be promising new drugs for II type diabetes.This thesis reports the design, synthesis, evaluation and structure-activity relationship analysis of a novel series of potential dual agonists for PPARα and PPARγ. The accomplished research work is highlighted as follows:1. By scrutinizing the structures of PPAR agonists and their binding mode to the receptors, we established a common U-shaped pharmacophore for the agonists of both receptors. It consists of a moiety responsible for hydrogen bonding net-work on one terminal, a hydrophobic and bulky fragment on the other end, and a flat and narrow linker between the two terminals.2. A novel virtual library of PPAR agonists was constructed based on a combinatorial strategy. The virtual building blocks A, B, and C were selected...