Research Project
7748570
DESCRIPTION (provided by applicant): The morbidity of obesity is a direct result of excess triglyceride accumulation, predominantly in adipose tissue and liver. Particularly in the liver, steatosis contributes to insulin resistance and Type II diabetes, and non- alcoholic steatohepatitis (NASH), which may progress to cirrhosis and liver failure. GPAT (glycerol-3- phosphate acyltransferase) is the initial committed step in acylglycerol synthesis and has garnered interest as a target for obesity and metabolic therapy. A number of GPAT isoform knockout mice have shown modest reduction in adipose tissue, and increased fatty acid oxidation, however, no pharmacological GPAT inhibitors have been reported. Under funding from Phase I and II SBIR grants for obesity research, FASgen has developed the first pharmacological GPAT inhibitors which are efficacious in diet-induced obese mice. FASgen has synthesized series of GPAT inhibitors encompassing multiple chemical scaffolds. We have completed a series of in vitro and in vivo preclinical studies demonstrating proof-of-principal for metabolic disease therapy. Our compounds: (a) inhibit GPAT activity in mitochondrial preparations, (b) preferentially inhibit triglyceride synthesis in 3T3-L1 adipocytes, (c) reversibly reduce weight and food intake in chronic treatment of DIO mice without toxicity, (d) increase fatty acid oxidation in DIO mice as measure by indirect calorimetry, (e) eliminate steatosis, normalize blood glucose, and reduce serum triglyceride levels in DIO mice, (f) increase expression of anorexigenic hypothalamic neuropeptides, and (g) enhance the expression of genes that favor fatty acid oxidation in liver and adipose tissue. The overall goal of this SBIR Phase II competitive renewal is to advance pharmacological GPAT inhibition towards commercialization. In this proposal we plan to [1] develop oral formulation for GPAT inhibitors, [2] finalize in vitro safety testing, [3] complete PK, CTA, and efficacy testing with DEXA adiposity measurements to select a lead compound [4] perform a 5-day rat TK study, [5] undergo cardiac testing in conscious dogs, and [6] conclude a formal 28-day preclinical GLP rat toxicity study. With these efficacy and safety data, we will schedule a pre-pre IND meeting with the FDA within 2 years. PUBLIC HEALTH RELEVANCE: Obesity and its associated diseases occur in epidemic proportions in the U.S., and are increasing worldwide. GPAT is a key enzyme in the pathway that synthesizes storage fat called triglyceride. FASgen has developed the first pharmacological inhibitors of GPAT that are effective in reducing weight in diet-induced obese mice. This grant will enable FASgen to rapidly move these compounds toward drug development.
