Development of potent indole-3-carboxamide autotaxin inhibitors with preferred lipophilicity for in vivo treatment of pulmonary fibrosis

Autotaxin (ATX), a major source of the lipid mediator lysophosphatidic acid (LPA), plays a critical role in the pathogenesis and progression of pulmonary fibrosis. In this study, with the aim of developing novel ATX inhibitors with preferred lipophilicity, structure-based optimizations of PAT-409 were carried out, leading to the identification of two novel orally active ATX inhibitors, 4 and 29, with IC50 values of 1.5 nM and 1.08 nM, respectively. Both compounds demonstrated favorable physicochemical properties and desirable ADMET profiles. Notably, compounds 4 and 29 exhibited excellent in vitro metabolic stability (t(1/2) > 170 min) and negligible cytotoxicity. Furthermore, oral administration of either compound 4 or 29 (60 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to PAT-409 (60 mg/kg) in a bleomycin-induced pulmonary fibrosis mouse model, suggesting their potential as promising anti-pulmonary fibrosis agents for further development.