Development of Oral Bioavailable Nicotinamide N-Methyltransferase Inhibitors to Reduce Adiposity, Insulin Resistance, and Hyperglycemia

There is a critical need for new mechanism-of-action drugs that reduce adiposity, a prime driver of type 2 diabetes. A novel target to treat adiposity and reverse type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in regulating adipose tissue metabolism and energy homeostasis. We have recently developed first-in-class small molecule NNMT inhibitors and characterized physicochemical, pharmacological, pharmacokinetic (PK), and off-target safety profiles of these inhibitors to identify a drug-like efficacious, orally bioavailable, and safe lead candidate for IND-enabling studies. Our first generation of highly selective, stable, and soluble compounds demonstrated excellent PK properties, including high oral bioavailability (>90%) and half-life of 3 hours in rats. Finally, the efficacy of promising NNMT inhibitors at modulating adiposity and type 2 diabetes endpoints (e.g., fat mass, oral glucose tolerance, adipokine levels, circulating lipids) were assessed using diet-induced obese (DIO) mice maintained on a high-fat diet. Systemic treatment of DIO mice with a potent NNMT inhibitor significantly reduced body weight and white adipose tissue mass, decreased adipocyte cell size, and lowered plasma cholesterol levels (p<0.05). Notably, administration of NNMT inhibitors did not alter total food intake nor produce any observable adverse effects. These results support continued development of small molecule NNMT inhibitors as therapeutics to lessen adiposity and lower the burden of adiposity-associated type 2 diabetes.