Rational design and identification of potent imidazole-fused Autotaxin inhibitors for treatment of idiopathic pulmonary fibrosis

Autotaxin (ATX) plays a critical role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis treatment. Herein, in pursuit of expanding the chemical space of novel ATX inhibitors, a series of imidazole-fused (imidazo[1,2-b]pyridazine and benzo[d]imidazole) derivatives with aliphatic amine linkers were designed through integrating the structural features of GLPG-1690 and PF-8380. Meanwhile, a terminal aromatic benzamide fragment was involved to penetrate the hydrophobic pocket. Following enzyme activity screening, compound 12 bearing N-(1H-benzo[d]imidazole-5-yl)furan-2-carboxamide showed the optimal in vitro ATX inhibitory activity (IC₅₀ = 46 nM), accompanied by favorable drug-like properties. The docking study well elucidated the promising activity of 12 for the key H-bond interactions with Trp261 and Ser170, as well as π-π interactions with Trp255 and Phe274. Significantly, in the Bleomycin-induced pulmonary fibrosis mouse model, 12 has certainly reduced Collagen deposition and ameliorated lung fibrosis. Overall, compound 12 turned out to be a well-characterized potent ATX inhibitor warranting further investigation for the treatment of idiopathic pulmonary fibrosis.