ABSTRACT
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Ketones/chemistry , Ketones/pharmacokinetics , Administration, Oral , Biological Availability , Cathepsin K , Cathepsins/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/administration & dosage , Humans , Ketones/administration & dosage , Protein Conformation , Structure-Activity RelationshipABSTRACT
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Subject(s)
Amides/chemical synthesis , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Ketones/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Binding Sites , Biological Availability , Bone Resorption/drug therapy , Bone Resorption/metabolism , Cathepsin K , Cathepsins/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Disease Models, Animal , Hypocalcemia/drug therapy , Hypocalcemia/metabolism , Ketones/pharmacokinetics , Ketones/pharmacology , Rats , Rats, Wistar , Solubility , Structure-Activity RelationshipABSTRACT
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.