During the period of support provided by Phase I of SBIR-AT-NIDDK, 50 compounds were evaluated as a basis for drug development. The most promising of these compounds have been evaluated in a series of carefully integrated in-vitro experiments using informative cell lines and in-vivo studies in lean and diet induced- obese (DIO) mice, with special emphasis placed on whole animal calorimetry. Distinct targets and mechanisms by which these compounds produce weight loss have been defined: 1) FAS1183 and 1057 inhibit FAS located in the specialized nuclei in the brain stem that control feeding behavior causing levels of AMPK to fall, the expression of neuropeptide Y (NPY) to decline and food intake to be restricted, leading to weight loss; 2) FAS2089B stimulates the activity of CPT-1 in peripheral tissues, especially adipose tissue, leading to an increased rate of FAO and the selective reduction in body fat; 3) FAS3169 and 3115 at by both mechanisms 1 and 2. We have recently found that C75 inhibits mitochondrial glycerol-3-acyltransferase (GPAT) which may lead to decreased fat storage and increased FAO as well. As a result of the work detailed in the progress report, 5 lead-candidates have been selected for final evaluation with a view toward identifying and formulating an experimental drug to be tested in Phase l-ll clinical trials supported by Phase II SBIR-AT funding. FASgen believes that it has demonstrated the feasibility of its approach to a small molecule based pharmacotherapy for obesity and thereby, satisfied the performance milestones set in Phase I of its SBIR-AT research grant. This SBIR Phase II proposal is designed to identify a developmental lead compound from amongst the five best candidates available at the initiation of the SBIR Phase II funding period, to collect the data required to file an IND and to initiate Phase l-ll safety and efficacy trials in humans. Amongst the final candidates will be at least one from each mechanistic category: e g CMS active (feeding suppressant), FAO stimulants and molecules with both activities. However, one should bear in mind that therapeutics based on each of the mechanisms may have a worthy use for the prescribing physician. For instance a dual acting compound may be the therapeutic of choice to treat a severely obese individual. Whereas a CMS active appetite suppressant may be the therapeutic of choice to maintain a more healthy weight once an individual has lost significant amounts of adipose tissue. ? ?
| Wydysh, Edward A; Vadlamudi, Aravinda; Medghalchi, Susan M et al. (2010) Design, synthesis, and biological evaluation of conformationally constrained glycerol 3-phosphate acyltransferase inhibitors. Bioorg Med Chem 18:6470-9 |
