Identification of new dual FABP4/5 inhibitors based on a naphthalene-1-sulfonamide FABP4 inhibitor
Identification of new dual FABP4/5 inhibitors based on a naphthalene-1-sulfonamide FABP4 inhibitor
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基于萘-1-磺酰胺 FABP4 抑制剂鉴定新型双 FABP4/5 抑制剂
DOI：
10.1016/j.bmc.2019.07.031
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发表时间：
2019
影响因子：
3.5
通讯作者：
Li Yingxia
中科院分区：
文献类型：
--
作者：
He Yulong;Dou Huixia;Gao Dingding;Wang Ting;Zhang Mingming;Wang Heyao;Li Yingxia
脂肪酸结合蛋白4 （FABP4）和脂肪酸结合蛋白5 （FABP5）主要表达于脂肪细胞和/或巨噬细胞中，在能量代谢和炎症反应中发挥重要作用。当FABP4功能减弱时，FABP5的表达高度增加，这可能是一种功能补偿。双FABP4/5抑制剂有望在治疗糖尿病、动脉粥样硬化和炎症相关疾病方面提供有益的协同作用。从我们之前报道的选择性FABP4抑制剂开始，我们利用结构生物学信息来调节选择性，并设计出对FABP3具有良好选择性的有效双FABP4/5抑制剂。发现两种化合物sa16和b8对FABP4/5均有抑制活性，对FABP3有良好的选择性，这也可以降低成熟3T3-L1脂肪细胞中forskolin刺激的脂肪分解水平。与化合物8相比，这两种化合物对脂多糖刺激的小鼠RAW264.7巨噬细胞具有更好的抗炎作用，可降低促炎细胞因子TNFα和MCP-1的水平，并明显抑制IKK/NF-κB通路。
Fatty acid binding protein 4 (FABP4) and fatty acid binding protein 5 (FABP5) are mainly expressed in adipocytes and/or macrophages and play essential roles in energy metabolism and inflammation. When FABP4 function is diminished, FABP5 expression is highly increased possibly as a functional compensation. Dual FABP4/5 inhibitors are expected to provide beneficial synergistic effect on treating diabetes, atherosclerosis, and inflammation-related diseases. Starting from our previously reported selective FABP4 inhibitor8, structural biology information was used to modulate the selectivity profile and to design potent dual FABP4/5 inhibitors with good selectivity against FABP3. Two compoundsA16andB8were identified to show inhibitory activities against both FABP4/5 and good selectivity over FABP3, which could also reduce the level of forskolin-stimulated lipolysis in mature 3T3-L1 adipocytes. Compared with compound8, these two compounds exhibited better anti-inflammatory effects in lipopolysaccharide-stimulated RAW264.7 murine macrophages, with decreased levels of pro-inflammatory cytokines TNFα and MCP-1 and apparently inhibited IKK/NF-κB pathway.