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 in vitro and in vivo 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 via 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.

辅因子烟酰胺腺嘌呤二核苷酸 (NAD ⁺ ) 在广泛的生理过程中起着关键作用，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) 激活剂已被证明可以增加体外和体内的NAD ⁺ 水平并在动物模型中证明有益效果。这些化合物中经过最佳验证的化合物在结构上与已知的尿素型 NAMPT 抑制剂相关，但是从抑制活性转变为激活的基础尚不清楚。在这里，我们通过设计、合成和测试来自其他 NAMPT 配体化学型的化合物和已知激活剂的假定磷酸核糖化加合物的模拟物，报告了对 NAMPT 激活剂结构活性关系的评估。这些研究的结果使我们假设这些激活剂通过NAMPT 活性位点中的透水相互作用，导致设计出第一个已知的不使用类吡啶弹头的尿素类 NAMPT 活化剂，其在生化和细胞测定中显示出与 NAMPT 活化剂相似或更高的活性已知的类似物。