Abstract
Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Administration, Oral
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Aldehydes / chemistry
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Animals
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Cardiovascular Diseases / drug therapy*
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Cardiovascular Diseases / enzymology*
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Crystallography, X-Ray
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Indazoles / chemistry
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / therapeutic use*
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Pyrimidines / administration & dosage
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Pyrimidines / chemistry*
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Pyrimidines / therapeutic use*
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Rats
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Structure-Activity Relationship
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rho-Associated Kinases / antagonists & inhibitors*
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rho-Associated Kinases / metabolism
Substances
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Aldehydes
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Indazoles
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Protein Kinase Inhibitors
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Pyrimidines
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Adenosine Triphosphate
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rho-Associated Kinases
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pyrimidine