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, neuro-degeneration, 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.