Abstract
A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
MeSH terms
-
Crystallography, X-Ray
-
Dose-Response Relationship, Drug
-
Drug Design
-
Humans
-
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
-
Mitogen-Activated Protein Kinase 14 / metabolism
-
Models, Molecular
-
Molecular Structure
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
-
Proto-Oncogene Proteins B-raf / metabolism
-
Structure-Activity Relationship
-
Urea / analogs & derivatives
-
Urea / chemistry
-
Urea / pharmacology*
-
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
-
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
-
Protein Kinase Inhibitors
-
Urea
-
KDR protein, human
-
Vascular Endothelial Growth Factor Receptor-2
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins B-raf
-
TNNI3K protein, human
-
Mitogen-Activated Protein Kinase 14