Discovery of Novel Autotaxin Inhibitors Bearing the 4,5,6,7-Tetrahydro-7H-Pyrazolo[3,4-c]Pyridine-7-One Core for Pulmonary Fibrosis Therapy

Pulmonary fibrosis (PF) is a progressive and fatal disease, and recent studies have revealed its key role in the autotaxin (ATX)-lysophosphatidic acid (LPA) signaling pathway, revealing the therapeutic potential of targeting ATX. Herein, starting from PAT-409, a series of novel ATX inhibitors containing the 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one core were designed to improve the pharmacological activity and physicochemical properties. The most promising compound 19 exhibited potent ATX inhibition (IC₅₀ = 4.2 nM) and significantly reduced lipophilicity (cLogP = 2.992) compared with PAT-409 (IC₅₀ = 4.9 nM, cLogP = 7.647). Molecular dynamics simulations indicated that 19 bound to the ATX protein in a highly stable manner. Furthermore, predictive analyses of drug-like properties and toxicity uncovered that 19 demonstrated comparable safety to PAT-409 while exhibiting significantly superior drug-like characteristics. This study provides a promising ATX inhibitor for PF therapy.