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Discovery of Novel N-Nicotinamide Methyltransferase Inhibitors to Combat Obesity-Linked Osteoarthritis and Metabolic Disease Among Veterans and Beneficiaries
Technical Report,30 Sep 2015,29 Sep 2016
University of Texas Medical Branch Galveston United States
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Nicotinamide N-methyltransferase NNMT has been implicated in osteoarthritis, metabolic disorders, cardiovascular disease,cancer, kidney disease, and Parkinsons disease that impact the military, their dependents, and the general population. Thisproject is developing drug candidates that specifically target NNMT and produce targeted reductions in white adipose tissue,leading to significant weight loss and improvements in obesity-linked comorbidities. Towards this end, we developed the firstassay to directly monitor NNMT product formation and activity in real-time, resulting in the enhanced capacity to collectaccurate NNMT kinetic data. Detailed kinetic data analysis has resulted in the detailed molecular characterization of NNMTreaction mechanism, and, importantly, discovery of novel drug-like nanomolar NNMT inhibitors. These drug candidates showed attractive cellular permeability flux when tested in membrane transport assays. Synthesis scale-up of the most promising drug candidates has been achieved. Proof-of-concept evaluation in mouse models of diet-induced obesity is awaiting final IACUC approval, but is anticipated to commence within the month.
APPROVED FOR PUBLIC RELEASE