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

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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5053573 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Wang Zhen Z Bian Huan H Bartual Sergio G SG Du Wenting W Luo Jinfeng J Zhao Hu H Zhang Shasha S Mo Cheng C Zhou Yang Y Xu Yong Y Tu Zhengchao Z Ren Xiaomei X Lu Xiaoyun X Brekken Rolf A RA Yao Libo L Bullock Alex N AN Su Jin J Ding Ke K

Journal of medicinal chemistry 20160603 12

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. ...[more]

PMID: 27219676

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Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors.

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