Discovery of triazolyl azabicyclo[3.1.0]hexane derivative as an autotaxin inhibitors for the treatment of pulmonary fibrosis.

Autotaxin (ATX), the enzyme responsible for generating lysophosphatidic acid (LPA), is a validated target for fibrosis and cancer immunotherapy. Current ATX inhibitors face challenges related to insufficient efficacy or safety concerns, reflecting trade-offs between zinc engagement and selectivity. Here, we report a rigid triazolyl-azabicyclo[3.1.0]hexanyl-oxadiazolyl-pyrimidine scaffold developed through structure-based design, designed to potentially enhance ATX selectivity by promoting defined binding geometry. Systematic studies identified 14e as the most potent inhibitor (IC50 = 14.2 nM in vitro; 0.7 nM in human plasma), showing low cytotoxicity and favorable pharmacokinetics. MD simulations suggested that 14e preferentially adopts an intrinsically rigid conformation, supporting a stable zinc-coordinating binding mode and optimal occupation of the ATX hydrophobic pocket. 14e produced strong target engagement with >97% suppression of plasma LPA18:2 ex vivo and demonstrated significant antifibrotic efficacy in the bleomycin-induced pulmonary fibrosis mouse model, reducing collagen deposition and inflammation. These results establish 14e as a promising lead scaffold for further development of ATX-targeted therapeutics.