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

J Med Chem. 2018 Feb 8;61(3):745-759. doi: 10.1021/acs.jmedchem.7b01254. Epub 2018 Jan 26.

Abstract

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 (IC50 = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxy-Lyases / antagonists & inhibitors*
  • Carboxy-Lyases / chemistry
  • Carboxy-Lyases / metabolism
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • NAD / biosynthesis*
  • Phenylacetates / metabolism
  • Phenylacetates / pharmacology
  • Protein Conformation

Substances

  • Enzyme Inhibitors
  • Phenylacetates
  • NAD
  • Carboxy-Lyases
  • aminocarboxymuconate-semialdehyde decarboxylase
  • phenylacetic acid