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-α (TNF-α) 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.
Highlights
Acute lung injury (ALI) is an inflammatory condition, which is characterized by accumulation of neutrophils in lung tissue.[1−3] ALI has clinically proven to be a leading cause of acute respiratory failure in critically ill patients for which standard treatment is mainly supportive due to lack of effective therapies.[4]
Discoidin domain receptors (DDRs), i.e., Discoidin Domain Receptor 1 (DDR1) and DDR2, are transmembrane receptor tyrosine kinases (RTKs), which were activated by triple-helical collagens.[7−9] DDR1 and DDR2 have been demonstrated to play critical roles in regulation of cellular morphogenesis, differentiation, proliferation, adhesion, migration, and invasion.[10−14] Increasing evidence has suggested the potential role of DDRs in regulation of secretion of inflammatory factors in atherosclerosis, organ fibrosis, and many other inflammatory disorders.[15,16]
A number of well-characterized kinase inhibitors were reported to potently suppress the functions of DDR1 and DDR2.14 few of them were developed by using DDR1 or DDR2 as the primary target
Summary
Acute lung injury (ALI) is an inflammatory condition, which is characterized by accumulation of neutrophils in lung tissue.[1−3] ALI has clinically proven to be a leading cause of acute respiratory failure in critically ill patients for which standard treatment is mainly supportive due to lack of effective therapies.[4]. When the methyl group was merged to R6 position, the resulting compound (7f) demonstrated 14-fold less potency aDDR1 and DDR2 experiments were performed using LANCE ULTRA kinase assay according to the manufacturer’s instructions.
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