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Molecules 2016, 21(2), 229; doi:10.3390/molecules21020229

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

1,* , 1,2
,
1
and
1
1
Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361102, China
2
Quality Responsibility Pharmaceuticals Co., Ltd., Wuhan Research & Development Center, Wuhan 430075, China
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 22 December 2015 / Revised: 12 February 2016 / Accepted: 14 February 2016 / Published: 18 February 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [942 KB, uploaded 18 February 2016]   |  

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. View Full-Text
Keywords: fatty acid amide hydrolase (FAAH); uracil derivatives; FAAH inhibitor; amidation fatty acid amide hydrolase (FAAH); uracil derivatives; FAAH inhibitor; amidation
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Qiu, Y.; Zhang, Y.; Li, Y.; Ren, J. Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase. Molecules 2016, 21, 229.

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