Tang Siyuan, Garzon Sanz Miguel, Smith Oliver, Krämer Andreas, Egbase Daniel, Caton Paul W, Knapp Stefan, Butterworth Sam
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK.
Structural Genomics Consortium (SGC), 60438 Frankfurt Am Main, Germany.
Acta Pharm Sin B. 2023 Feb;13(2):709-721. doi: 10.1016/j.apsb.2022.07.016. Epub 2022 Aug 1.
The cofactor nicotinamide adenine dinucleotide (NAD) plays a key role in a wide range of physiological processes and maintaining or enhancing NAD levels is an established approach to enhancing healthy aging. Recently, several classes of nicotinamide phosphoribosyl transferase (NAMPT) activators have been shown to increase NAD levels and and to demonstrate beneficial effects in animal models. The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors, however the basis for the switch from inhibitory activity to activation is not well understood. Here we report an evaluation of the structure activity relationships of NAMPT activators by designing, synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators. The results of these studies led us to hypothesise that these activators act a through-water interaction in the NAMPT active site, resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead, which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.
辅助因子烟酰胺腺嘌呤二核苷酸（NAD）在广泛的生理过程中起关键作用，维持或提高NAD水平是促进健康衰老的既定方法。最近，几类烟酰胺磷酸核糖基转移酶（NAMPT）激活剂已被证明可提高NAD水平，并在动物模型中显示出有益效果。这些化合物中验证最充分的在结构上与已知的尿素型NAMPT抑制剂相关，然而从抑制活性转变为激活活性的基础尚不清楚。在此，我们通过设计、合成和测试来自其他NAMPT配体化学类型的化合物以及已知激活剂的推定磷酸核糖基化加合物的模拟物，报告了对NAMPT激活剂构效关系的评估。这些研究结果使我们推测，这些激活剂通过与NAMPT活性位点的水相互作用发挥作用，从而设计出了第一种已知的不使用吡啶样弹头的尿素类NAMPT激活剂，该激活剂在生化和细胞试验中作为NAMPT激活剂表现出与已知类似物相似或更高的活性。
