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

  • Eur J Med Chem. 2025 Nov 15:298:118011. doi: 10.1016/j.ejmech.2025.118011.
Bing Zhao  1 ,  Sha Xu  1 ,  Xiujian Wei  1 ,  You Li  1 ,  Shiyi Qu  1 ,  Hongrui Lei  2 ,  Xin Zhai  3
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China. Electronic address: [email protected].
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China. Electronic address: [email protected].
PMID: 40738079 DOI: 10.1016/j.ejmech.2025.118011
Abstract

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.

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