Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation

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.