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

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

Open Access

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

Author(s) -

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

Publication year - 2016

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.6b00140

Subject(s) - discoidin domain , chemistry , ddr1 , tetrahydroisoquinoline , kinase , pharmacology , ic50 , structure–activity relationship , stereochemistry , biochemistry , in vitro , receptor tyrosine kinase , medicine

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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