Download MendeleyDesign, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2.
Wang, Z., Zhang, Y., Pinkas, D.M., Fox, A.E., Luo, J., Huang, H., Cui, S., Xiang, Q., Xu, T., Xun, Q., Zhu, D., Tu, Z., Ren, X., Brekken, R.A., Bullock, A.N., Liang, G., Ding, K., Lu, X.(2018) J Med Chem 61: 7977-7990
- PubMed: 30075624
- DOI: https://doi.org/10.1021/acs.jmedchem.8b01045
- Primary Citation of Related Structures:
6GWR - PubMed Abstract:
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 d values of 7.9 and 8.0 nM; potently inhibited the kinases with IC 50 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.
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.
Organizational Affiliation:
