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

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Synthesis, Optimization, and Structure–Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-14 , DOI: 10.1021/acs.jmedchem.3c01406
Zhengnan Shen ₁ , Kiira Ratia _{2,

3} , Isabella Krider ₄ , Martha Ackerman-Berrier ₁ , Christopher Penton ₁ , Soumya Reddy Musku ₁ , Jesse M Gordon-Blake ₂ , Megan S Laham ₄ , Nicholas Christie ₄ , Nina Ma ₁ , Jiqiang Fu ₁ , Rui Xiong ₁ , Jenna M Courey ₄ , Ganga Reddy Velma ₁ , Gregory R J Thatcher _{1,

4}

Affiliation

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.

中文翻译：

烟酰胺磷酸核糖转移酶（NAMPT）正变构调节剂（N-PAM）的合成、优化和构效关系

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以补充 NAD⁺。NAD⁺ 分解代谢为烟酰胺（NAM）需要挽救 NAM 以补充细胞 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膳食补充剂的替代品。筛选 NAMPT 激活剂确定了小分子 NAMPT 阳性变构调节剂（N-PAM）。N-PAM 与 NAMPT 的后通道结合，增加酶活性并减轻 NAM 和 NAD⁺ 的反馈抑制。超过 70 个 N-PAM 的合成提供了后通道结合亲和力与酶激活效力之间的极好相关性，证实了通过与后通道结合的变构激活机制。该机制导致较高的结合亲和力导致疗效丧失。酶激活直接转化为在细胞中测量的 NAD⁺ 升高。优化导致口服生物可利用的 N-PAM。

更新日期：2023-12-14

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