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Bioorg Med Chem Lett. 2011 May 15;21(10):2949-52. doi: 10.1016/j.bmcl.2011.03.063. Epub 2011 Mar 22.

New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein.

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1
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.

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.

PMID:
21481589
DOI:
10.1016/j.bmcl.2011.03.063
[Indexed for MEDLINE]

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