Discovery of a pyrano[2,3-b]pyridine derivative YX-2102 as a cannabinoid receptor 2 agonist for alleviating lung fibrosis

Abstract Background Pharmacological modulation of cannabinoid 2 receptor (CB2R) is a promising therapeutic strategy for pulmonary fibrosis (PF). Thus, to develop CB2R selective ligands with new chemical space has attracted much research interests. This work aims to discover a novel CB2R agonist from an in-house library, and to evaluate its therapeutic effects on PF model, as well as to disclose the pharmacological mechanism. Methods Virtual screening was used to identify the candidate ligand for CB2R from a newly established in-house library. Both in vivo experiments on PF rat model and in vitro experiments on cells were performed to investigate the therapeutic effects of the lead compound and underlying mechanism. Results A “natural product-like” pyrano[2,3-b]pyridine derivative, YX-2102 was identified that bound to CB2R with high affinity. Intraperitoneal YX-2102 injections significantly ameliorated lung injury, inflammation and fibrosis in a rat model of PF induced by BLM. YX-2102 significantly upregulated CB2R expression in alveolar epithelial cells in vivo. Moreover, YX-2102 pretreatment inhibited lung alveolar epithelial-to-mesenchymal transition (EMT) in vitro (and PF model induced by TGF-β1) via a CB2 receptor-dependent pathway. Further studies suggested that the Nrf2-Smad7 pathway might be involved in. Conclusion These findings suggest that CB2R is a potential target for PF treatment and YX-2102 is a promising CB2R agonist with new chemical space.