Bioorganic & Medicinal Chemistry Letters
Optimization of a urea-containing series of nicotinamide
phosphoribosyltransferase (NAMPT) activators
,
Anthony B. Pinkertona *, E. Hampton Sessionsa, Paul Hershbergera, Patrick R. Maloneya,
Satyamaheshwar Peddibhotlaa, Meghan Hopfd, Eduard Sergienkoa, Chen-Ting Maa,
Layton H. Smitha, Michael R. Jacksona, Jun Tanakab, Takashi Tsujib, Mayuko Akiub,
Steven E. Cohenc, Tsuyoshi Nakamurab, Stephen J. Gardelld
a Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
b R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
c Daiichi Sankyo, Inc., Global Business Development, Basking Ridge, NJ 07920, USA
d Translational Research Institute. AdventHealth, Orlando, FL 32804, USA
A R T I C L E I N F O
A B S T R A C T
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 phos-
phoribosyltransferase (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:
NAMPT
NAMPT activators
NAD+ booster
Ureas
Nicotinamide adenine dinucleotide (NAD+) is involved in diverse
cellular processes that govern human health and disease.1 NAD+ has
long been known as a redox enzyme cofactor. More recently, NAD+ was
shown to be a co-substrate for sirtuins and poly-ADP-ribose polymerases
(PARPs) which has unveiled pivotal roles in cell signaling, DNA repair,
cell division, and epigenetics.2,3 Increased tissue levels of NAD+ have
been shown to mediate beneficial effects in a variety of preclinical dis-
ease models.4 These findings have spurred keen interest in pharmaco-
logical and nutraceutical strategies that boost intracellular NAD+
levels.5,6
(PRPP). In turn, NMNAT produces NAD+ from NMN.
NAMPT, a homodimeric type II phosphoribosyltransferase, is the
putative rate-limiting step in the NAM salvage pathway.8
Enzymology9–11 and X-ray crystallograph12–15 studies have yielded a
detailed understanding of NAMPT catalytic activity. NAMPT has also
been shown to be the dominant route for NAD+ synthesis in the heart
and kidney16, with preclinical data suggesting that NAD+ repletion
strategies have the potential to aid in the treatment of cardiac and
kidney injuries, possibly by maintaining sirtuin activity.5 Additionally,
early evidence may show beneficial effects of NAM supplementation in
some forms of eye disease.17,18 Conversely, potent and highly selective
NAMPT inhibitors have been developed and evaluated as a treatment for
cancer.19
NAD+ is consumed in cells due to the actions of sirtuins, PARPs and
NADases.7 Hence, cellular NAD+ biosynthetic pathways are obligatory
to preserve the NAD+ levels which are required for cell viability. The
dominant NAD+ synthetic route in most mammalian cells is the nico-
tinamide (NAM) salvage pathway involving sequential actions of nico-
We recently reported the discovery of SBI-0797812 (2), a small
molecule NAMPT activator which was generated from the HTS hit SBI-
0136892 (1; Fig. 1).20 Interestingly, SBI-0797812 (2) was recently
shown to exert an antiviral effect due to its ability to modulate innate
immunity.21 While SBI-0797812 displayed acceptable potency, its ro-
dent pharmacokinetic (PK) properties, including oral bioavailability
tinamide
phosphoribosyltransferase
(NAMPT)
and
NMN
adenylyltransferase (NMNAT). NAMPT forms nicotinamide mono-
nucleotide (NMN) and pyrophosphate (PP) from NAM (produced by
sirtuins and PARPs) and
α-D-5-phosphoribosyl-1-pyrophosphate
* Corresponding author.
Received 19 January 2021; Received in revised form 25 March 2021; Accepted 27 March 2021
Available online 31 March 2021
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