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烟酰胺磷酸核糖基转移酶（NAMPT）正变构调节剂（N-PAMs）的合成、优化及构效关系。

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

机构信息

Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.

出版信息

J Med Chem. 2023 Dec 28;66(24):16704-16727. doi: 10.1021/acs.jmedchem.3c01406. Epub 2023 Dec 14.

DOI:10.1021/acs.jmedchem.3c01406
PMID:38096366
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10758216/
Abstract

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.

摘要

烟酰胺腺嘌呤二核苷酸 (NAD) 的消耗与衰老和疾病有关，这促使人们研究膳食补充剂来补充 NAD。NAD 代谢为烟酰胺 (NAM) 需要回收 NAM 来补充细胞内的 NAD，这依赖于限速酶烟酰胺磷酸核糖转移酶 (NAMPT)。NAMPT 的药理学激活提供了替代膳食补充剂的方法。筛选 NAMPT 的激活剂鉴定出小分子 NAMPT 正变构调节剂 (N-PAM)。N-PAM 结合到 NAMPT 的后通道，增加酶活性并减轻 NAM 和 NAD 的反馈抑制。合成了 70 多种 N-PAM，为后通道结合亲和力与酶激活效力之间提供了极好的相关性，证实了通过结合后通道进行变构激活的机制。该机制解释了更高的结合亲和力导致效力丧失。酶激活直接转化为细胞内 NAD 水平的升高。优化导致一种可口服生物利用的 N-PAM。

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2
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3
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4
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