piperidines and Idiopathic-Pulmonary-Fibrosis

Ifenprodil (

Topics: Antifibrinolytic Agents; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; Idiopathic Pulmonary Fibrosis; Models, Molecular; Molecular Structure; Piperidines; Receptors, N-Methyl-D-Aspartate; Stereoisomerism; Structure-Activity Relationship

The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound

Topics: Animals; Bleomycin; Crystallography, X-Ray; DNA; Dogs; Humans; Hydantoins; Idiopathic Pulmonary Fibrosis; Lung; Male; Mice, Inbred C57BL; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Protein Binding; Rats; Spiro Compounds

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with high mortality rate. The etiology is unknown and treatment choices are limited. Thus, there is great interest to investigate novel agents for IPF therapy. Ibrutinib, BTK, and ITK irreversible inhibitor is a FDA-approved small molecule for the clinical therapy of B cell lymphoma. Its role in pulmonary fibrosis remains unknown. In this study, we investigated the anti-fibrotic activity of ibrutinib. Strikingly, ibrutinib did not inhibit but exacerbated bleomycin-induced pulmonary fibrosis by increased epithelial cell apoptosis, and inflammation in the lung. The upregulated TGF-β and EMT transformation also contributes to enhanced myofibroblast differentiation and ECM deposition. Our findings reveal the detrimental effects of ibrutinib against bleomycin-mediated fibrosis and added to the understanding of IPF pathogenesis.

Topics: Adenine; Animals; Apoptosis; Bleomycin; Disease Models, Animal; Epithelial Cells; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Mice; Piperidines; Pulmonary Fibrosis; Pyrazoles; Pyrimidines

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug Hypersensitivity; Drug Substitution; Humans; Idiopathic Pulmonary Fibrosis; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Quinazolines; Spirometry; Vascular Endothelial Growth Factor Receptor-2