Structure-based identification of novel pyrrolo[2,3-d]pyrimidine analogs as potent autotaxin inhibitors

In recent decades, it has been well established that the down-regulation of the autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway showed considerable effectiveness in treating various diseases. In order to develop novel potent ATX inhibitors, a series of pyrrolo[2,3-d]pyrimidine derivatives (G1 similar to G22) were designed and synthesized based on the molecular docking of PAT-409 with ATX protein. All compounds were selected for ATX inhibitory activity studies in vitro to extend the structure-activity relationship (SAR) study. To our delight, some compounds displayed preferable activity against ATX enzyme. Among them, compound G18 with a typical N-4-(hydroxyphenyl)acetamide hydrophilic "tail" showed the most excellent activity against ATX with IC50 values of 8.1 nM, exceeding that of PAT-409 (IC50 = 9.8 nM). Meanwhile, G18 was endowed with superior druglikeness properties, making it a promising therapeutic agent for the treatment of ATX-driven diseases.