Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 8, Pages 1653-1664Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.02.013
Keywords
Xanthine oxidase; NOD-like receptor 3; Toll-like receptor 4; Anti-hyperuricemia; Gout
Funding
- National Natural Science Foundation of China [81202573, 81773745]
- Suzhou Science & Technology Foundation [SYS201665]
- PAPD - Priority Academic Program Development of Jiangsu Higher Education Institutions
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Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and antiacute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD. (c) 2018 Elsevier Ltd. All rights reserved.
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