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

Bioorg Med Chem Lett. 2021 Jun 1:41:128007. doi: 10.1016/j.bmcl.2021.128007. Epub 2021 Mar 31.

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.

Keywords: NAD(+) booster; NAMPT; NAMPT activators; Ureas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemistry
  • Urea / pharmacology*

Substances

  • Cytokines
  • Urea
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human