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

Pinkerton, Anthony B.; Sessions, E. Hampton; Hershberger, Paul; Maloney, Patrick; 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.

doi:10.1016/j.bmcl.2021.128007

Cited by 12 publications

(13 citation statements)

References 24 publications

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“…As a result of the limitations in our understanding of the activity of 6 and related NA-site binding activators, we sought to investigate the structure–activity relationships around this compound in more detail by preparing analogues based on the following design criteria: To date, the published examples of NAMPT-activators from the NA-site binding class are based on the urea-like scaffold of 6 17 , 18 , 19 . Crystal structures of closely related inhibitors such as 2 demonstrate a similar binding mode to FK866 and triazole-based NAMPT inhibitors, we therefore designed and synthesised compounds 7 and 8 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To date, the published examples of NAMPT-activators from the NA-site binding class are based on the urea-like scaffold of 6 17 , 18 , 19 . Crystal structures of closely related inhibitors such as 2 demonstrate a similar binding mode to FK866 and triazole-based NAMPT inhibitors, we therefore designed and synthesised compounds 7 and 8 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…There appears to be a specific requirement for a pyridine-like nitrogen at the 4-position of 6 , with the phenyl analogue being inactive and the 3-pyridyl being a known NAMPT inhibitor. This pyridine-like nitrogen is also present in all urea-class NAMPT activators reported in later publications, wherein the 3-pyridine has been modified to heterocyclic systems including pyrazoles and isoxazoles, alongside modifications in other regions that can enhance both activity and selectivity of these compounds 17 , 18 , 19 . This finding has been followed by the discovery of further NAMPT-activator chemotypes that do not bind in the NA site, however the pyridine/azole urea molecules remain the most fully biologically characterised molecules 20 .…”

Section: Introductionmentioning

confidence: 93%

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Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators

Tang

Sanz

Smith

et al. 2023

Acta Pharmaceutica Sinica B

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators

Tang

Sanz

Smith

et al. 2023

Acta Pharmaceutica Sinica B

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“…The pyridine nitrogen was shifted from position 4 in SBI-797812 to position 2 or 3 to change the compound from NAMPT activator to inhibitor ( Gardell et al, 2019 ). The resulting compound 43 showed more efficient NAMPT activation (EC 50 = 0.023 μM) and improved oral bioavailability ( Pinkerton et al, 2021 ). DS68702229 (compound 44 ) was identified as a potent NAMPT activator (EC 50 = 0.046 μM) that increases cellular NAD + levels and is a promising anti-obesity drug candidate ( Akiu et al, 2021a ).…”

Section: Current Progress Of Nicotinamide Phosphoribosyltransferase-b...mentioning

confidence: 99%

From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases

Zhu

Huang

et al. 2022

Front. Pharmacol.

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Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD) salvage pathway in mammals. It is of great significance in the metabolic homeostasis and cell survival via synthesizing nicotinamide mononucleotide (NMN) through enzymatic activities, serving as a key protein involved in the host’s defense mechanism. The NAMPT metabolic pathway connects NAD-dependent sirtuin (SIRT) signaling, constituting the NAMPT–NAD–SIRT cascade, which is validated as a strong intrinsic defense system. Neurodegenerative diseases belong to the central nervous system (CNS) disease that seriously endangers human health. The World Health Organization (WHO) proposed that neurodegenerative diseases will become the second leading cause of human death in the next two decades. However, effective drugs for neurodegenerative diseases are scant. NAMPT is specifically highly expressed in the hippocampus, which mediates cell self-renewal and proliferation and oligodendrocyte synthesis by inducing the biosynthesis of NAD in neural stem cells/progenitor cells. Owing to the active biological function of NAMPT in neurogenesis, targeting NAMPT may be a powerful therapeutic strategy for neurodegenerative diseases. This study aims to review the structure and biological functions, the correlation with neurodegenerative diseases, and treatment advance of NAMPT, aiming to provide a novel idea for targeted therapy of neurodegenerative diseases.

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“…Contrary to tumor transformation, metabolic and cardiovascular diseases, as well as neurodegenerative disorders, are associated with a marked decline in NAD levels, and boosting NAD biosynthesis has emerged as a potential therapeutic approach for their treatment [ 18 , 19 ]. Small molecule activators of NAMPT, which are effective in increasing intracellular NAD levels and result in strong neuroprotective efficacy in pre-clinical models, have been developed [ 20 , 21 ]. Regarding NAPRT, activation of the enzyme by substrate supplementation in cultured cells was shown to boost NAD levels and decrease cytotoxicity induced by oxidative stress [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Properly Substituted Benzimidazoles as a New Promising Class of Nicotinate Phosphoribosyltransferase (NAPRT) Modulators

et al. 2023

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The prevention of nicotinamide adenine dinucleotide (NAD) biosynthesis is considered an attractive therapeutic approach against cancer, considering that tumor cells are characterized by an increased need for NAD to fuel their reprogrammed metabolism. On the other hand, the decline of NAD is a hallmark of some pathological conditions, including neurodegeneration and metabolic diseases, and boosting NAD biosynthesis has proven to be of therapeutic relevance. Therefore, targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD biosynthesis from nicotinamide (NAM) and nicotinic acid (NA), respectively, is considered a promising strategy to modulate intracellular NAD pool. While potent NAMPT inhibitors and activators have been developed, the search for NAPRT modulators is still in its infancy. In this work, we report on the identification of a new class of NAPRT modulators bearing the 1,2-dimethylbenzimidazole scaffold properly substituted in position 5. In particular, compounds 24, 31, and 32 emerged as the first NAPRT activators reported so far, while 18 behaved as a noncompetitive inhibitor toward NA (Ki = 338 µM) and a mixed inhibitor toward phosphoribosyl pyrophosphate (PRPP) (Ki = 134 µM). From in vitro pharmacokinetic studies, compound 18 showed an overall good ADME profile. To rationalize the obtained results, docking studies were performed on the NAPRT structure. Moreover, a preliminary pharmacophore model was built to shed light on the shift from inhibitors to activators.

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

Cited by 12 publications

References 24 publications

Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators

Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators

From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases

Properly Substituted Benzimidazoles as a New Promising Class of Nicotinate Phosphoribosyltransferase (NAPRT) Modulators

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