Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Yan QiuJie Ren

Abstract

Fatty Acid Amide Hydrolase (FAAH) is an intracellular serine enzyme involved in the biological degradation of the fatty acid ethanolamide family of signaling lipids, which exerts neuroprotective, anti-inflammatory, and analgesic properties. In the present study, a conjugated 2,4-dioxo-pyrimidine-1-carboxamide scaffold was confirmed as a novel template for FAAH inhibitors, based on which, a series of analogues had been prepared for an initial structure-activity relationship (SAR) study. Most of the synthesized compounds displayed moderate to significant FAAH inhibitory potency. Among them, compounds 11 and 14 showed better activity than others, with IC50 values of 21 and 53 nM. SAR analysis indicated that 2,4-dioxopyrimidine-1-carboxamides represented a novel class of potent inhibitors of FAAH, and substitution at the uracil ring or replacement of the N-terminal group might favor the inhibitory potency. Selected compounds of this class may be used as useful parent molecules for further investigation.

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Citations

Apr 16, 2020·Expert Opinion on Drug Discovery·Domenico FazioMauro Maccarrone
Jan 17, 2020·European Journal of Medicinal Chemistry·Rati Kailash Prasad Tripathi
Jul 3, 2021·Polymers·Maresa SonnabendMarc C Leimenstoll

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Methods Mentioned

BETA
amidation
column chromatography
MDS
NMR
protein assay

Software Mentioned

GraphPad Prism
GraphPad

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