The Specific Aim of this proposal is to test the feasibility of using an orally available small molecule (FGH10019) to reduce obesity. Obesity contributes to the prevalence of many disease states and accounts for more than 25% of all health care costs in the US according to recent market reports. Prescription pharmaceuticals account for less than 1 percent of the total obesity market because of limited efficacy, poorly understood biology and significant safety issues. We have discovered a diarylthiazole compound that inhibits insulin-mediated adipogenesis by blocking SREBP-1 and 2. Administration of the compounds to obese ob/ob mice led to weight loss, marked reduction of visceral fat, increased insulin sensitivity, and lower blood glucose levels. We have since improved the drug properties of this original compound. Our current lead compound is FGH10019, which has higher potency in blocking SREBP-1 and 2, has improved oral bio-availability in mice, and other improved drug like properties. FGH10019 is effective in reducing weight and improving hyperglycemia in Ob/Ob mice. However, before moving to IND enabling studies, must evaluate this compound in a small animal model that more closely resembles human obesity. In this Phase I study, we will therefore test efficacy of our compound in a high fat diet rat model. To this end, we will carry out the following Tasks: Task 1: Evaluate maximum tolerated dose (MTD) by oral gavage of FGH-10019 to Sprague-Dawley rats. Task 2: Evaluate dose to reduce weight gain and lower triglycerides, LDL and blood glucose. Test of Feasibility: we must observe: 1) MTD at or greater than 100 mg/kg; 2) significant effective dose at 1/10 or 1/5 the MTD and we must observe reduced weight by 8%, due to decrease in fat content, improved hyperglycemia and lowering LDL and TG by more than 25%, without affecting HDL. In Phase II, we will move FGH 10019 toward IND enabling studies and search for improved back-up compounds. PUBLIC HEALTH RELEVANCE: Obesity and related disorders currently account for almost 25% of the total healthcare budget and the problem is getting worse as rates of obesity continue to increase. Diet and exercise are the mainstays of weight loss programs, but in most cases they are not sufficient to address the problem. Prescription drugs are generally of limited use and they can exhibit serious side effects. This is a proposal to develop a truly effective drug tha acts through a novel mechanism for effectively treating obesity and related disorders.