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 journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7977-7990
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number17
DOIs
StatePublished - Sep 13 2018

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Anti-Inflammatory Agents
Drug Discovery
Lipopolysaccharides
Phosphotransferases
Acute Lung Injury
Inhibitory Concentration 50
Interleukin-6
Fibroblasts
Western Blotting
Lung
Discoidin Domain Receptor 1
benzamide
Discoidin Domain Receptor 2
Lead
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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.; Fox, Alice E.; Luo, Jinfeng; Huang, Huocong; Cui, Shengyang; Xiang, Qiuping; Xu, Tingting; Xun, Qiuju; Zhu, Dongsheng; Tu, Zhengchao; Ren, Xiaomei; Brekken, Rolf A.; Bullock, Alex N.; Liang, Guang; Ding, Ke; Lu, Xiaoyun.

In: Journal of Medicinal Chemistry, Vol. 61, No. 17, 13.09.2018, p. 7977-7990.

Research output: Contribution to journalArticle

Wang, Zhen ; Zhang, Yali ; Pinkas, Daniel M. ; Fox, Alice E. ; Luo, Jinfeng ; Huang, Huocong ; Cui, Shengyang ; Xiang, Qiuping ; Xu, Tingting ; Xun, Qiuju ; Zhu, Dongsheng ; Tu, Zhengchao ; Ren, Xiaomei ; Brekken, Rolf A. ; Bullock, Alex N. ; Liang, Guang ; Ding, Ke ; Lu, Xiaoyun. / 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. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 17. pp. 7977-7990.
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AU - Brekken, Rolf A.

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AU - Ding, Ke

AU - Lu, Xiaoyun

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