Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 proteins with K values of 7.9 and 8.0 nM; potently inhibited the kinases with IC values of 9.4 and 20.4 nM, respectively; and was significantly less potent for a panel of 403 wild-type kinases at 1.0 μM. DDR1- and DDR2-kinase inhibition by 5n was validated by Western-blotting analysis in primary human lung fibroblasts. The compound also dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release in vitro and exhibited promising in vivo anti-inflammatory effects in an LPS-induced-acute-lung-injury (ALI) mouse model. Compound 5n may serve as a lead compound for new anti-inflammatory drug discovery.
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| http://dx.doi.org/10.1021/acs.jmedchem.8b01045 | DOI Listing |
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