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

[Display omitted] 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...

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Published in:Bioorganic & medicinal chemistry letters 2021-06, Vol.41, p.128007-128007, Article 128007
Main Authors: Pinkerton, Anthony B., Sessions, E. Hampton, Hershberger, Paul, Maloney, Patrick R., Peddibhotla, Satyamaheshwar, Hopf, Meghan, Sergienko, Eduard, Ma, Chen-Ting, Smith, Layton H., Jackson, Michael R., Tanaka, Jun, Tsuji, Takashi, Akiu, Mayuko, Cohen, Steven E., Nakamura, Tsuyoshi, Gardell, Stephen J.
Format: Article
Language:English
Subjects:
NAD+ booster
NAMPT
NAMPT activators
Ureas
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2021.128007