Abstract
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
MeSH terms
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Animals
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Antihypertensive Agents / chemical synthesis*
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Antihypertensive Agents / pharmacokinetics
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Antihypertensive Agents / pharmacology
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Aorta / drug effects
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Aorta / physiology
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Blood Pressure / drug effects
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Models, Molecular
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Muscle Contraction / drug effects
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiology
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Oxadiazoles / chemical synthesis*
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Oxadiazoles / pharmacokinetics
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Oxadiazoles / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Rats
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Rats, Inbred SHR
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Structure-Activity Relationship
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rho-Associated Kinases
Substances
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Antihypertensive Agents
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Benzimidazoles
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Intracellular Signaling Peptides and Proteins
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Oxadiazoles
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Protein Serine-Threonine Kinases
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rho-Associated Kinases