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.
Bioorg Med Chem Lett. 2011 May 15;21(10):2949-52. doi: 10.1016/j.bmcl.2011.03.063. Epub 2011 Mar 22.
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.
脂肪型脂肪酸结合蛋白（a-FABP）在炎症反应中不可或缺，可能成为治疗炎症相关疾病的新潜在药物靶点。我们成功设计并合成了一系列芳香取代的吡唑类化合物，作为新型人源脂肪型脂肪酸结合蛋白（a-FABP）抑制剂。这些化合物与 a-FABP 的疏水结合口袋有很强的结合能力，而对密切相关的同源蛋白 h-FABP 的结合亲和力则显著降低。最有效和选择性的化合物 5g 与 a-FABP 的表观 K(i) 值低于 1.0 nM，而在 50 μM 时不抑制 h-FABP，因此是迄今为止最有效和选择性的 a-FABP 抑制剂之一。这些抑制剂的强结合能力通过其在 LPS 刺激下产生促炎细胞因子时有效阻断炎症反应得到进一步验证。化合物 5g 可能成为开发预防和治疗动脉粥样硬化、2 型糖尿病和其他炎症及代谢相关疾病的新型有效治疗药物的先导化合物。
