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

ABSTRACT: 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 Kd 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-? (TNF-?) 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.

SUBMITTER: Wang Z 

PROVIDER: S-EPMC5346979 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Wang Zhen Z   Zhang Yali Y   Bartual Sergio G SG   Luo Jinfeng J   Xu Tingting T   Du Wenting W   Xun Qiuju Q   Tu Zhengchao Z   Brekken Rolf A RA   Ren Xiaomei X   Bullock Alex N AN   Liang Guang G   Lu Xiaoyun X   Ding Ke K  

ACS medicinal chemistry letters 20170209 3

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 <b>7ae</b> was discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with a <i>K</i><sub>d</sub> value of 2.2 nM and an IC<sub>50</sub> value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccha  ...[more]

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