title: Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase.
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.
authors.affiliation: Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361102, China. yanqiu@xmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361102, China. zhyang880105@163.com.|Quality Responsibility Pharmaceuticals Co., Ltd., Wuhan Research &amp; Development Center, Wuhan 430075, China. zhyang880105@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361102, China. mfaoxmu@126.com.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361102, China. renjie_7912@xmu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000737:chemistry*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014498:Uracil; D000099252:Fatty Acid Amide Hydrolases
keywords: FAAH inhibitor; amidation; fatty acid amide hydrolase (FAAH); uracil derivatives