Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy

Wang, Leibo; Liu, Minghui; Zu, Yumeng; Hong, Yao; Wu, Chou; Zhang, Ruoxi; Ma, Weinan; Lu, Haigen; Xi, Shuang; Liu, Yang; Hua, Lan; Wang, Gelin; Tang, Yefeng

doi:10.1016/j.ejmech.2022.114260

Cited by 14 publications

(19 citation statements)

References 53 publications

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“…The mechanism we have proposed for NAMPT activation by N-PAMs is intrinsically linked to the concentration of NAM. The comparison of NAMPT activation induced by N-PAMs ( 9 , 43 , and 63 ), NAT1, and SBI-797812 shows activation dependent on NAM concentration (Figure C). ,, …”

Section: Resultsmentioning

confidence: 93%

“…The phenol NAT-5r, reported as an optimized derivative of NAT1, binds to NAMPT with higher affinity (Figure 2B; K d = 570 nM). 41 The binding affinity of NAT-5r is comparable to the higher efficacy NP-A1 derivatives and suggests that the mechanism of NAMPT activation may be similar.…”

Section: Assay Of Binding Affinity Informed By Cocrystalmentioning

confidence: 90%

“…The synthetic phenol NAT1 was recently reported as a NAMPT activator. 41 NAT1 was studied as a neuroprotective agent in a mouse model. The first compound claimed to be a NAMPT activator, P7C3-A20, was studied in a similar mouse model.…”

Section: Assay Of Binding Affinity Informed By Cocrystalmentioning

confidence: 99%

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Synthesis, Optimization, and Structure–Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs)

Shen,

Ratia,

Krider

et al. 2023

J. Med. Chem.

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Depletion of nicotinamide adenine dinucleotide (NAD + ) is associated with aging and disease, spurring the study of dietary supplements to replenish NAD + . The catabolism of NAD + to nicotinamide (NAM) requires the salvage of NAM to replenish cellular NAD + , which relies on the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological activation of NAMPT provides an alternative to dietary supplements. Screening for activators of NAMPT identified small molecule NAMPT positive allosteric modulators (N-PAMs). N-PAMs bind to the rear channel of NAMPT increasing enzyme activity and alleviating feedback inhibition by NAM and NAD + . Synthesis of over 70 N-PAMs provided an excellent correlation between rear channel binding affinity and potency for enzyme activation, confirming the mechanism of allosteric activation via binding to the rear channel. The mechanism accounts for higher binding affinity leading to loss of efficacy. Enzyme activation translated directly to elevation of NAD + measured in cells. Optimization led to an orally bioavailable N-PAM.

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Section: Resultsmentioning

confidence: 93%

Section: Assay Of Binding Affinity Informed By Cocrystalmentioning

confidence: 90%

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Synthesis, Optimization, and Structure–Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs)

Shen,

Ratia,

Krider

et al. 2023

J. Med. Chem.

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“…NAT-5r showed a K D value of 132 nM and an EC 50 value of 2.6 μM. This is the first study on the structure-activity relationship of NAMPT activator based on the co-crystal structure (Wang et al, 2022). NAT-5r can increase intracellular NAD levels and induce subsequent metabolic and transcriptional reprogramming.…”

Section: Nicotinamide Phosphoribosyltransferase Agonists In Developmentmentioning

confidence: 86%

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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“…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: 99%

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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Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy

Cited by 14 publications

References 53 publications

Synthesis, Optimization, and Structure–Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs)

Synthesis, Optimization, and Structure–Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs)

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

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

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