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New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein |
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| Authors: | Liu Xiujie Huang Xiaoli Lin Wanhua Wang Dongye Diao Yanyan Li Honglin Hui Xiaoyan Wang Yu Xu Aimin Wu Donghai Ke Ding |
| Institution: | a Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, PR China b Graduate School of Chinese Academy of Sciences, PR China c Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China d Department of Medicine and Pharmacology, University of Hong Kong, Pok Fu Lam Road, Hong Kong 999077, China |
| Abstract: | a-FABP is indespensible in inflammation and may serve as a new potential drug target for inflammation related diseases. We have successfully designed and synthesized a series of aromatic substituted pyrazoles as new human a-FABP inhibitors. The compounds strongly bound to the hydrophobic binding pocket of a-FABP, while showed significantly lower binding affinities to the closely related homologue protein h-FABP. The most potent and selective compound 5g bound to a-FABP with an apparent Ki value below 1.0 nM, while did not inhibit h-FABP at 50 μM and thus represents one of the most potent and selective a-FABP inhibitors to date. The strong binding capacity of these inhibitors was further validated by their effective blockade of inflammatory responses as determined by the production of pro-inflammatory cytokines upon LPS stimulation. Compound 5g may serve as a lead compound for developing new effective therapeutic agent for prevention and treatment of atherosclerosis, type 2 diabetes and other inflammatory and metabolic related diseases. |
| Keywords: | a-FABP inhibitor Aromatic substituted pyrazoles Inflammatory response Inflammation related diseases |
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