Researchers from China proposed a new compound called compound 47 as a potential candidate for further development for the treatment of idiopathic pulmonary fibrosis (IPF).
The compound strongly inhibits discoidin domain receptors 1 and 2 and has low toxicity, good pharmacokinetic properties, and reliable in vivo antifibrosis efficacy, the authors said in a study published in Acta Pharmaceutica Sinica B.
Even though the US Food and Drug Administration (FDA) approved pirfenidone and nintedanib for the treatment of IPF, neither has been shown to be very effective in treating the disease. Previous research has shown that discoidin domain receptor inhibitors have antifibrotic effects and could therefore have potential therapeutic effects in IPF.
Here, the team extensively optimized their previous multikinase inhibitors and discovered a series of more selective discoidin domain receptor inhibitors including compound 47.
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They showed that this compound had potent activity against discoidin domain receptors 1 and 2. It also reduced the activity of platelet-derived growth factor receptors, fibroblast growth factor receptors, and kinase-insert domain-containing receptors. These properties made it less toxic than nintedanib.
Moreover, using in vitro studies, they showed that compound 47 reduced bleomycin-induced lung injury, as well as inflammation and pulmonary fibrosis.
Finally, it could restrict the activation of myofibroblasts during lung fibrosis by inhibiting the transforming growth factor beta-induced activation of protein kinase beta and focal adhesion kinase.
All of these properties make compound 47 a potential candidate for further development to be used as a treatment for IPF. Compound 47 is a 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamide.
Wang Q, Tang B, Sun D, et al. Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis. Acta Pharm Sin B. Published online November 17, 2021. doi:10.1016/j.apsb.2021.11.012