Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators.
Basic Information
ID: ALA4814043
Journal: Bioorg Med Chem Lett
Title: Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators.
Authors: Pinkerton AB, Sessions EH, Hershberger P, Maloney PR, Peddibhotla S, Hopf M, Sergienko E, Ma CT, Smith LH, Jackson MR, Tanaka J, Tsuji T, Akiu M, Cohen SE, Nakamura T, Gardell SJ.
Abstract: 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.
CiteXplore: 33798699
DOI: 10.1016/j.bmcl.2021.128007
Patent ID: ┄