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

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

doi:10.1021/acs.jmedchem.8b01045

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

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

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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 IC₅₀ 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.

Original language	English (US)
Pages (from-to)	7977-7990
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01045
State	Published - Sep 13 2018

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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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). 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. Journal of Medicinal Chemistry, 61(17), 7977-7990. https://doi.org/10.1021/acs.jmedchem.8b01045

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. / Wang, Zhen; Zhang, Yali; Pinkas, Daniel M. et al.
In: Journal of Medicinal Chemistry, Vol. 61, No. 17, 13.09.2018, p. 7977-7990.

Research output: Contribution to journal › Article › peer-review

Wang, Z, Zhang, Y, Pinkas, DM, Fox, AE, Luo, J, Huang, H, Cui, S, Xiang, Q, Xu, T, Xun, Q, Zhu, D, Tu, Z, Ren, X, Brekken, RA, Bullock, AN, Liang, G, Ding, K & Lu, X 2018, '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', Journal of Medicinal Chemistry, vol. 61, no. 17, pp. 7977-7990. https://doi.org/10.1021/acs.jmedchem.8b01045

Wang Z, Zhang Y, Pinkas DM, Fox AE, Luo J, Huang H et al. 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. Journal of Medicinal Chemistry. 2018 Sep 13;61(17):7977-7990. doi: 10.1021/acs.jmedchem.8b01045

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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 Kd values of 7.9 and 8.0 nM; potently inhibited the kinases with IC50 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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AU - Wang, Zhen

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AU - Ren, Xiaomei

AU - Brekken, Rolf A.

AU - Bullock, Alex N.

AU - Liang, Guang

AU - Ding, Ke

AU - Lu, Xiaoyun

PY - 2018/9/13

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N2 - 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 Kd values of 7.9 and 8.0 nM; potently inhibited the kinases with IC50 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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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

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