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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5911-5916
Number of pages6
JournalJournal of Medicinal Chemistry
Volume59
Issue number12
DOIs
StatePublished - Jun 23 2016

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Tetrahydroisoquinolines
Phosphotransferases
Pulmonary Fibrosis
Therapeutic Uses
Inhibitory Concentration 50
Pharmacokinetics
Discoidin Domain Receptor 1
indium-bleomycin
1,2,3,4-tetrahydroisoquinoline

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. / Wang, Zhen; Bian, Huan; Bartual, Sergio G.; Du, Wenting; Luo, Jinfeng; Zhao, Hu; Zhang, Shasha; Mo, Cheng; Zhou, Yang; Xu, Yong; Tu, Zhengchao; Ren, Xiaomei; Lu, Xiaoyun; Brekken, Rolf A.; Yao, Libo; Bullock, Alex N.; Su, Jin; Ding, Ke.

In: Journal of Medicinal Chemistry, Vol. 59, No. 12, 23.06.2016, p. 5911-5916.

Research output: Contribution to journalArticle

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
Wang, Zhen ; Bian, Huan ; Bartual, Sergio G. ; Du, Wenting ; Luo, Jinfeng ; Zhao, Hu ; Zhang, Shasha ; Mo, Cheng ; Zhou, Yang ; Xu, Yong ; Tu, Zhengchao ; Ren, Xiaomei ; Lu, Xiaoyun ; Brekken, Rolf A. ; Yao, Libo ; Bullock, Alex N. ; Su, Jin ; Ding, Ke. / Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 12. pp. 5911-5916.
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AU - Luo, Jinfeng

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