Discovery of novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo

• Published in: European journal of medicinal chemistry Vol. 275; p. 116608
• Main Authors: Li, Yanchun, Yang, Huali, Zhao, Xiangling, Zhao, Xianchen, Quan, Jishun, Wang, Lei, Ma, Enlong, Ma, Chao
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-09-2024
• Subjects: Animals; Bleomycin; Dose-Response Relationship, Drug; Drug Discovery; HDAC6; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Idiopathic pulmonary fibrosis (IPF); Idiopathic Pulmonary Fibrosis - chemically induced; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - pathology; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Mouse model; Pharmacological mechanism; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Selectivity; Structure-Activity Relationship; Selectivity; Mouse model; Idiopathic pulmonary fibrosis (IPF); Pharmacological mechanism; HDAC6
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116608

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment. The best-performing derivative H10 showed good selectivity for multiple isoforms of the HDAC family. The structural analysis and structure-activity relationship studies of H10 will contribute to optimizing the binding mode of the new molecules. The pharmacological mechanism of H10 to inhibit pulmonary fibrosis was validated, and its ability to inhibit the IPF phenotype was also demonstrated. Moreover, H10 showed satisfactory metabolic stability. The efficacy of H10 was also determined in a mouse model of bleomycin-induced pulmonary fibrosis. The results highlighted in this paper may provide a reference for the identification of new drug molecules for the treatment of IPF.
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•A series of novel HDAC6 inhibitors was identified that can be used for the treatment of idiopathic pulmonary fibrosis (IPF).•Compounds H4 and H10 showed good and comparable HDAC6 inhibition potential, but H10 showed better selectivity for HDAC6.•The therapeutic activity of H10 for idiopathic pulmonary fibrosis (IPF) has been demonstrated in vitro and in vivo.•H10 showed satisfactory metabolic stability.