Discovery of Novel N-Nicotinamide Methyltransferase Inhibitors to Combat Obesity-Linked Osteoarthritis and Metabolic Disease Among Veterans and Beneficiaries
Abstract
Nicotinamide N-methyltransferase (NNMT) has been implicated in osteoarthritis, metabolic disorders, cardiovascular disease, cancer, kidney disease, and Parkinson's disease that impact the military, their dependents, and the general population. This project 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 first assay to directly monitor NNMT product formation and activity in real-time, resulting in the enhanced capacity to collect accurate NNMT kinetic data. Detailed kinetic data analysis has resulted in the detailed molecular characterization of NNMT reaction 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 has been completed and shows promising activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2018
- Accession Number
- AD1059191
Entities
People
- Stanley J Watowich
Organizations
- University of Texas Medical Branch