New Agents That Inhibit Fatty Acid Accumulation
DESCRIPTION (provided by applicant): Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. Existing treatments for obesity are only modestly effective. The mission of AdipoGenix, Inc. is to discover and develop novel therapeutics acting on the fat cell, an approach that is likely to be effective in treating obesity and related metabolic disorders. We have identified a potent compound that inhibits fatty acid accumulation in differentiated human preadipocytes. In Phase I, we determined that this compound, AGX- 0104, is a PPARgamma antagonist. Importantly, this compound exhibits a favorable species-dependent potency, with a >1000-fold lower ICs0 in human adipocytes compared to murine adipocytes. AGX-0104 represents a suitable candidate for pre-clinical development in Phase II. We will screen related compounds in our primary fatty acid accumulation assay to obtain a detailed structure-activity relationship (SAR), and will advance selected compounds through lead optimization and preliminary in vivo studies. Two approaches to the SAR analysis will be carried out in parallel: 1) focused compound libraries will be synthesized to screen for improved compound potency, and 2) specific structural modifications to the parent chemotype will be made to abolish irreversible binding to the target. Selected compounds will be evaluated in cell-based transcriptional activation assays and in in vitro PPARgamma binding studies. Effects of these compounds on expression of adipogenic markers and in metabolic assays for fatty acid oxidation, triglyceride synthesis and lipolysis will be examined. Specificity toward fat depot will be assessed. We will commence pre-clinical evaluation of the selected compounds for solubility, cytotoxicity and efficacy in the primary screen in murine and rat preadipocytes. Assays to rule out induction of DNA damage and to determine cell permeability and metabolic stability will be performed. A lead compound will be chosen for further evaluation in protein binding and cytochrome P450 inhibition studies, and will proceed to compound scale-up and purification for use in preliminary in vivo rodent studies. Bioavailability and toxicity will be evaluated, and effectiveness of the lead compound in protecting against diet-induced weight gain in rodents will be studied. These efforts are expected to yield a potent, selective compound with 'drug-like' properties for further development and an IND filing. Development of this compound series may lead to novel therapeutic agents that are effective for modulating lipid metabolism and treating obesity.
Small Business Information at Submission:
ADIPOGENIX, INC. 801 ALBANY ST, S112 BOSTON, MA 02119
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