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

被引：37

作者：

Wang, Zhen ^{[1
,2
]}

Zhang, Yali ^{[3
]}

Bartual, Sergio G. ^{[5
]}

Luo, Jinfeng ^{[2
]}

Xu, Tingting ^{[4
]}

Du, Wenting ^{[6
,7
]}

Xun, Qiuju ^{[2
]}

Tu, Zhengchao ^{[2
]}

Brekken, Rolf A. ^{[6
,7
]}

Ren, Xiaomei ^{[2
]}

Bullock, Alex N. ^{[5
]}

Liang, Guang ^{[3
]}

Lu, Xiaoyun ^{[1
]}

Ding, Ke ^{[1
]}

机构：

[1] Jinan Univ, Sch Pharm, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China

[2] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, 190 Kaiyuan Ave, Guangzhou 510530, Guangdong, Peoples R China

[3] Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou, Peoples R China

[4] Wenzhou Med Univ, Affiliated Hosp 2, Dept Pulm Med, Wenzhou, Peoples R China

[5] Univ Oxford, Struct Genom Consortium, Old Rd Campus,Roosevelt Dr, Oxford OX3 7DQ, England

[6] UT Southwestern Med Ctr, Div Surg Oncol, Dept Surg, Dallas, TX 75390 USA

[7] UT Southwestern Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 03期

基金：

中国国家自然科学基金; 巴西圣保罗研究基金会; 英国惠康基金; 加拿大创新基金会;

关键词：

DDR1; inhibitor; structure-activity relationship (SAR); inflammation; acute lung injury (ALI); KINASE INHIBITORS; TYROSINE KINASES; COLLAGEN; DISCOVERY; IDENTIFICATION; DISEASE; BINDING; POTENT; MICE;

D O I：

10.1021/acsmedchemlett.6b00497

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Acute lung injury (ALI) is a deadly symptom for serious lung inflammation. Discoidin Domain Receptor 1 (DDR1) is a new potential target for anti-inflammatory drug discovery. A new selective tetrahydroisoquinoline-7-carboxamide based DDR1 inhibitor 7ae was discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with a K-d value of 2.2 nM and an IC50 value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) release in mouse primary peritoneal macrophages (MPMs). In addition, 7ae also exhibited promising in vivo anti-inflammatory effects in a LPS-induced mouse ALI model. To the best of our knowledge, this is the first "proof of concept" investigation on the potential application of a small molecule DDR1 inhibitor to treat ALI.

引用

页码：327 / 332

页数：6

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