期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 243, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114703
关键词
CCL20/CCR6; IBDs; Chemotaxis; TNBS-induced colitis; Peritonitis; Small-molecules
资金
- University of Parma
- Luxembourg Institute of Health
- European Crohn's and Colitis Organisation
- Luxembourg National Research Fund [7.8504.20]
- FNRS Televie [7.4593.19, CA 18133]
- [INTER/FNRS/20/15084569]
- [7.8508.22]
The study identifies a new pharmacological approach for the treatment of inflammatory bowel diseases (IBDs) based on small-molecule CCR6 antagonists. The most promising compound was identified using in silico studies and in vitro assays and its efficacy was validated in mouse models. This research provides a theoretical foundation for the development of orally bioavailable drugs for the treatment of IBD and other diseases regulated by the CCL20/CCR6 axis.
The CCL20/CCR6 axis is implicated in the migration of CCR6+ immune cells towards CCL20, its sole ligand, whose expression is increased during inflammatory processes and is known to play a pivotal role in triggering different autoimmune-mediated inflammatory diseases. Herein, we report a drug discovery effort focused on the development of a new pharmacological approach for the treatment of inflammatory bowel diseases (IBDs) based on small-molecule CCR6 antagonists. The most promising compound 1b was identified by combining in silico studies, sustainable chemistry and in vitro functional/targeted assays, and its efficacy was finally validated in a classic murine model of colitis (TNBS-induced) and in a model of peritonitis (zymosan-induced). These data provide the proof of principle that a pharmacological modulation of the CCL20/CCR6 axis may indeed represent the first step for the development of an orally bioavailable drug candidate for the treatment of IBD and, potentially, other diseases regulated by the CCL20/CCR6 axis.
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