Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-β1 pathway.
Li X, Lu C, Liu S, Shuaishuai Liu, Su C, Xiao T, Bi Z, Sheng P, Huang M, Liu X, Wei Y, Zhao L, Miao S, Mao J, Huang K, Gao S, Liu N, Qi M, Liu T, Qin S, Wei L, Sun T, Ning W, Yang G, Zhou H, Yang C.
In this study, anti-IPF lead compounds 42 and 44, derived from natural sesquiterpene lactones Isoalantolactone and alantolactone, were discovered by screening from a high-throughput TGF-β1 reporter luciferase assay. Notably, they could reduce the myofibroblast activation and extracellular matrix deposition both in vitro and in vivo. Additionally, compounds 42 and 44 could significantly attenuate bleomycin-induced pulmonary fibrosis in mice. Further validation of pharmacokinetics study and toxicity evaluation indicated that compound 44 might be a promising anti-IPF drug candidate.