Design, 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 | Zendy

Zhen Wang | Zendy; Yali Zhang | Zendy; Daniel M. Pinkas | Zendy; Alice E. Fox | Zendy; Jinfeng Luo | Zendy; Huocong Huang | Zendy; Shengyang Cui | Zendy; Qiuping Xiang | Zendy; Tingting Xu | Zendy; Qiuju Xun | Zendy; Dongsheng Zhu | Zendy; Zhengchao Tu | Zendy; Xiaomei Ren | Zendy; Rolf A. Brekken | Zendy; Alex N. Bullock | Zendy; Guang Liang | Zendy; Ke Ding | Zendy; Xiaoyun Lu | Zendy

Open Access

Design, 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

Author(s) -

Zhen Wang,

Yali Zhang,

Daniel M. Pinkas,

Alice E. Fox,

Jinfeng Luo,

Huocong Huang,

Shengyang Cui,

Qiuping Xiang,

Tingting Xu,

Qiuju Xun,

Dongsheng Zhu,

Zhengchao Tu,

Xiaomei Ren,

Rolf A. Brekken,

Alex N. Bullock,

Guang Liang,

Ke Ding,

Xiaoyun Lu

Publication year - 2018

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.8b01045

Subject(s) - chemistry , benzamide , in vivo , lead compound , ddr1 , kinase , pharmacology , discoidin domain , in vitro , jurkat cells , ic50 , drug discovery , stereochemistry , biochemistry , receptor tyrosine kinase , immunology , medicine , microbiology and biotechnology , immune system , t cell , biology

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.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.

Having issues? You can contact us here

Accelerating Research