SBIR-STTR Award

Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. Although weight loss is the most effective treatment for type 2 diabetes, current methods for reducing weight typically are insufficient for long-term weight loss. The mission of AdipoGenix, Inc. is to discover, develop and license novel therapeutics acting at the level of the fat cell (adipocyte) for the treatment of obesity and related disorders. Effective therapeutics, particularly those acting on the fat cell, is lacking. AdipoGenix already has developed advanced methods for culturing and differentiating human preadipocytes, and has established and validated a primary screening assay to monitor lipid accumulation in these cells. Using this assay 70,000 compounds were screened, and a new class of compounds that reduces lipid accumulation in differentiated human preadipocytes was identified. The present goal is to determine the mechanism of action by which these new compounds reduce lipid accumulation in order to facilitate further development of this class of compounds and to expand proprietary protection of our leads. In Aim 1 sufficient quantities of the lead and two related compounds will be synthesized for work in Aims 2 and 3. Radiolabeled lead compound also will be synthesized for use in Aim 2. In Aim 2 specific binding in homogenates from differentiated human preadipocytes using the unlabeled and radiolabeled compounds generated in Aim 1 will be determined. General receptor and mechanism of action screens also will be performed to identify the receptor and elucidate the cellular target mechanism by which these compounds reduce lipid accumulation in human adipocytes. In Aim 3 metabolic pathway analysis will be performed. Using this approach this new class of compounds has been shown not to act through PPARgamma or by stimulating lipolysis. Also in Aim 3, signaling pathways will be defined by analysis of focused signaling-pathway expression arrays using mRNA from differentiated human preadipocytes treated with our compounds. This work will produce key information to expedite receptor identification, determine mechanism of action, facilitate full lead optimization for the further development of this class of compounds, and to develop additional, new antiobesity drugs acting at the level of the fat cell.

Public Health Relevance Statement:


Project Terms:
biological signal transduction; obesity; chemical synthesis; polymerase chain reaction; nuclear magnetic resonance spectroscopy; adipocyte; pharmacokinetics; fatty acid; prostaglandin; human tissue; lead; radiotracer; receptor; tissue /cell culture; technology /technique development; clinical research; biotherapeutic agent; liquid chromatography mass spectrometry; cardiovascular disorder risk; diabetes risk

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.

Public Health Relevance Statement:


Project Terms:
Rodentia; obesity; chemical structure function; chemical synthesis; polymerase chain reaction; adipocyte; chemotherapy; pharmacology; inhibitor /antagonist; pharmacokinetics; drug screening /evaluation; drug design /synthesis /production; fatty acid; human subject; western blotting; tissue /cell culture; toxicology; clinical research; combinatorial chemistry; biotherapeutic agent; peroxisome proliferator activated receptor; patient oriented research