title: New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein.
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 5 g bound to a-FABP with an apparent K(i) 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 5 g 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.
authors.affiliation: 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.
authors.forename: Xiujie
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.forename: Wanhua
authors.initials: W
authors.lastname: Lin
authors.forename: Dongye
authors.initials: D
authors.lastname: Wang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Diao
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hui
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.forename: Ding
authors.initials: D
authors.lastname: Ke
mesh_terms: D017667:Adipocytes / Q000187:drug effects*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D050556:Fatty Acid-Binding Proteins; D011720:Pyrazoles