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.
Anthony B Pinkerton  1 ,  E Hampton Sessions  2 ,  Paul Hershberger  2 ,  Patrick R Maloney  2 ,  Satyamaheshwar Peddibhotla  2 ,  Meghan Hopf  3 ,  Eduard Sergienko  2 ,  Chen-Ting Ma  2 ,  Layton H Smith  2 ,  Michael R Jackson  2 ,  Jun Tanaka  4 ,  Takashi Tsuji  4 ,  Mayuko Akiu  4 ,  Steven E Cohen  5 ,  Tsuyoshi Nakamura  4 ,  Stephen J Gardell  3
Affiliations
  • 1. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 2. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 3. Translational Research Institute. AdventHealth, Orlando, FL 32804, USA.
  • 4. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5. Daiichi Sankyo, Inc., Global Business Development, Basking Ridge, NJ 07920, USA.
PMID: 33798699 DOI: 10.1016/j.bmcl.2021.128007
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.
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