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.
Subject(s)
Antihypertensive Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Aorta/drug effects , Aorta/physiology , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Blood Pressure/drug effects , In Vitro Techniques , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , rho-Associated KinasesABSTRACT
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.