Journal of Medicinal Chemistry p. 4090 - 4106 (2020)
Update date:2022-08-15
Topics: Inhibitors Highly potent
Su, Haixia
Zou, Yi
Chen, Guofeng
Dou, Huixia
Xie, Hang
Yuan, Xiaojing
Zhang, Xianglei
Zhang, Naixia
Li, Minjun
Xu, Yechun
Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ?460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.
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