α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD) Biosynthesis.

NAD has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of de novo NAD biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC = 0.013 μM) that increases NAD levels in cellular systems. The results of physicochemical-property, ADME, and safety profiling, coupled with in vivo target-engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD biosynthesis and position 22 as a first-class molecule for the evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD supply or homeostasis.