ABSTRACT
The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
Subject(s)
Amines/chemistry , Cholesterol/metabolism , Macrophages/drug effects , Orphan Nuclear Receptors/agonists , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Humans , Liver X Receptors , Macrophages/immunology , Mice , Mice, Knockout , Orphan Nuclear Receptors/genetics , Orphan Nuclear Receptors/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.
