α-Amino-ß-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis.
J Med Chem
; 61(3): 745-759, 2018 02 08.
Article
en En
| MEDLINE
| ID: mdl-29345930
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carboxiliasas
/
Inhibidores Enzimáticos
/
NAD
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia