α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) Inhibitors as Novel Modulators of de novoNicotinamide 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. Whilst the beneficial effects of NAD+boosting are well established in mitochondrial fitness, metabolism, and lifespan, 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 (IC50= 0.013 µM) that increase NAD+levels in cellular systems. Results of physicochemical properties, 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 in class molecule for evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD+supply and/or homeostasis.