Discovery of a Nicotinamide Phosphoribosyltransferase (NAMPT) Activator for Improving Muscle Function and Alleviating Fatigue.

Nicotinamide adenine dinucleotide (NAD+) plays a crucial role in cellular energy metabolism, and nicotinamide phosphoribosyltransferase (NAMPT) is the key rate-limiting enzyme in the NAD+ biosynthesis. Herein, we designed and synthesized a series of novel pyridine-based NAMPT activators to elevate NAD+ levels and counteract muscle fatigue. Among them, compound B11 demonstrated significant NAMPT activation activity, which effectively boosted NAD+ synthesis across multiple cell lines. Mechanistic studies revealed that compound B11 enhances glucose uptake and ATP production in C2C12 myotubes. In mouse fatigue models, compound B11 significantly improved exercise endurance and muscle strength of mice. These functional gains were accompanied by reduced lactate accumulation, enhanced hepatic and muscle glycogen storage, and elevated tissue ATP production. Importantly, compound B11 exhibited potential protective effects against fatigue-induced muscle damage, with favorable safety profiles. In summary, B11 represents a promising lead compound for the treatment of muscle fatigue.