Abstract
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.
MeSH terms
-
Amides / chemical synthesis*
-
Amides / pharmacokinetics
-
Amides / pharmacology
-
Animals
-
Antihypertensive Agents / chemical synthesis*
-
Antihypertensive Agents / pharmacokinetics
-
Antihypertensive Agents / pharmacology
-
Aorta / drug effects
-
Aorta / physiology
-
Blood Pressure / drug effects
-
In Vitro Techniques
-
Indazoles / chemical synthesis*
-
Indazoles / pharmacokinetics
-
Indazoles / pharmacology
-
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
-
Intracellular Signaling Peptides and Proteins / chemistry
-
Models, Molecular
-
Muscle Contraction / drug effects
-
Muscle, Smooth, Vascular / drug effects
-
Muscle, Smooth, Vascular / physiology
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / chemistry
-
Pyridones / chemical synthesis*
-
Pyridones / pharmacokinetics
-
Pyridones / pharmacology
-
Pyrimidines / chemical synthesis
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Rats
-
Rats, Inbred SHR
-
Structure-Activity Relationship
-
rho-Associated Kinases
Substances
-
Amides
-
Antihypertensive Agents
-
Indazoles
-
Intracellular Signaling Peptides and Proteins
-
Pyridones
-
Pyrimidines
-
Protein Serine-Threonine Kinases
-
rho-Associated Kinases