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

  • Eur J Med Chem. 2025 Apr 15:288:117398. doi: 10.1016/j.ejmech.2025.117398.
Deyi Ma  1 ,  Nan Jiang  1 ,  Jiachen Zhang  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, China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 39983555 DOI: 10.1016/j.ejmech.2025.117398
Abstract

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 (t1/2 > 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.

Keywords
1H-indole-3-carboxamide derivatives; Autotaxin; Inhibitors; Pulmonary fibrosis.
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