Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

Zhen Wang; Huan Bian; Sergio G. Bartual; Wenting Du; Jinfeng Luo; Hu Zhao; Shasha Zhang; Cheng Mo; Yang Zhou; Yong Xu; Zhengchao Tu; Xiaomei Ren; Xiaoyun Lu; Rolf A. Brekken; Libo Yao; Alex N. Bullock; Jin Su; Ke Ding

doi:10.1021/acs.jmedchem.6b00140

Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

Zhen Wang, Huan Bian, Sergio G. Bartual, Wenting Du, Jinfeng Luo, Hu Zhao, Shasha Zhang, Cheng Mo, Yang Zhou, Yong Xu, Zhengchao Tu, Xiaomei Ren, Xiaoyun Lu, Rolf A. Brekken, Libo Yao, Alex N. Bullock, Jin Su, Ke Ding

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Abstract

The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a K_d value of 4.7 nM and suppresses its kinase activity with an IC₅₀ value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model.

Original language	English (US)
Pages (from-to)	5911-5916
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	12
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00140
State	Published - Jun 23 2016

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Wang, Z., Bian, H., Bartual, S. G., Du, W., Luo, J., Zhao, H., Zhang, S., Mo, C., Zhou, Y., Xu, Y., Tu, Z., Ren, X., Lu, X., Brekken, R. A., Yao, L., Bullock, A. N., Su, J., & Ding, K. (2016). Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. Journal of Medicinal Chemistry, 59(12), 5911-5916. https://doi.org/10.1021/acs.jmedchem.6b00140

Wang, Z, Bian, H, Bartual, SG, Du, W, Luo, J, Zhao, H, Zhang, S, Mo, C, Zhou, Y, Xu, Y, Tu, Z, Ren, X, Lu, X, Brekken, RA, Yao, L, Bullock, AN, Su, J & Ding, K 2016, 'Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors', Journal of Medicinal Chemistry, vol. 59, no. 12, pp. 5911-5916. https://doi.org/10.1021/acs.jmedchem.6b00140

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abstract = "The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model.",

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doi = "10.1021/acs.jmedchem.6b00140",

language = "English (US)",

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AU - Du, Wenting

AU - Luo, Jinfeng

AU - Zhao, Hu

AU - Zhang, Shasha

AU - Mo, Cheng

AU - Zhou, Yang

AU - Xu, Yong

AU - Tu, Zhengchao

AU - Ren, Xiaomei

AU - Lu, Xiaoyun

AU - Brekken, Rolf A.

AU - Yao, Libo

AU - Bullock, Alex N.

AU - Su, Jin

AU - Ding, Ke

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Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

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