Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators

NAD⁺ is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD⁺ have been linked to numerous diseases including metabolic disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD⁺ is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD⁺ salvage pathway. We previously showed that NAMPT activators increase NAD⁺ levels in vitro and in vivo. Herein we describe the optimization of our NAMPT activator prototype (SBI-0797812) leading to the identification of 1-(4-((4-chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea (34) that showed far more potent NAMPT activation and improved oral bioavailability.