- Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors
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Fatty acid amide hydrolase (FAAH) is one of the key enzymes involved in the biological degradation of endocannabinoids, especially anandamide. Pharmacological blockage of FAAH restores the levels of endocannabinoids, providing therapeutic benefits in the management of inflammation, depression and multiple sclerosis. In this study, a series of uracil urea derivatives as FAAH inhibitors were designed and synthesized. Structural modifications at the C5 position and side chain of N-hexyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-carboxamide (1a) led to FAAH inhibitors with improved potency and selectivity. Structure-activity relationship (SAR) studies indicated that C5 electron-withdrawing substituents were preferred for optimal potency but not for selectivity, whereas replacement of the alkyl chain with phenylalkyl moieties or biphenyl groups significantly improved both inhibitory potency and selectivity towards FAAH. Two highly potent picomolar FAAH inhibitors (4c, IC50 = 0.3 ± 0.05 nM; 4d, IC50 = 0.8 ± 0.1 nM) were developed. Compound 4c inhibited FAAH in a rapid, selective, noncompetitive, and irreversible pattern. This study provides several highly potent and selective FAAH inhibitors and an optimized chemical scaffold for the development of FAAH inhibitors. We anticipate that these FAAH inhibitors will enable new possibilities in understanding FAAH functions and development of therapeutics for pain and inflammatory diseases.
- Qiu, Yan,Ren, Jie,Ke, Hongwei,Zhang, Yang,Gao, Qi,Yang, Longhe,Lu, Canzhong,Li, Yuhang
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p. 22699 - 22705
(2017/07/10)
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- ALKYL-, ACYL-, UREA-, AND AZA-URACIL SULFIDE:QUINONE OXIDOREDUCTASE INHIBITORS
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This application discloses compounds and pharmaceutical compositions and methods of using the same for inhibition of sulfide:quinone oxidoreductase (SQOR).
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Paragraph 0055; 0056
(2017/08/07)
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- Carbamyl uracil derivative and application thereof
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The invention discloses a carbamyl uracil derivative and application thereof. The structural formula of the derivative is as shown in the description. The derivative is a novel compound with the endogenous cannabinoid hydrolase inhibiting function, and a new method is provided for inflammation and pain treatment.
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Paragraph 0057; 0058; 0065; 0066
(2016/10/09)
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- 1-Carbamoyl-5-fluorouracil derivatives
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1-Carbamoyl-5-fluorouracil derivatives represented by the formula STR1 wherein R represents alkyl containing 3-8 carbon atoms are effective oral anti-tumor agents with low toxicity.
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