ABSTRACT
Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.
Subject(s)
Aspartic Acid/metabolism , Cytochrome P-450 CYP3A/metabolism , Protease Inhibitors/chemistry , Renin/antagonists & inhibitors , Aspartic Acid/chemistry , Binding Sites , Crystallography, X-Ray , Cytochrome P-450 CYP3A/chemistry , Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/metabolism , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protein Binding , Renin/metabolism , Structure-Activity RelationshipABSTRACT
A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent. The cellular potency of selected analogs is also described.
Subject(s)
Azepines/chemistry , Cathepsins/antagonists & inhibitors , Niacinamide/analogs & derivatives , Protease Inhibitors/chemistry , Alanine/chemistry , Azepines/chemical synthesis , Azepines/pharmacology , Binding Sites , Cathepsin K/antagonists & inhibitors , Cathepsin K/metabolism , Cathepsin L/antagonists & inhibitors , Cathepsin L/metabolism , Cathepsins/metabolism , Computer Simulation , Humans , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Azepines/chemical synthesis , Bone Density Conservation Agents/chemical synthesis , Cathepsins/antagonists & inhibitors , Sulfones/chemical synthesis , Animals , Azepines/chemistry , Azepines/pharmacology , Biological Availability , Blood Proteins/metabolism , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacology , Cathepsin K , Cathepsins/chemistry , Cell Line , Cell Membrane Permeability , Crystallography, X-Ray , Haplorhini , Humans , Molecular Conformation , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.
Subject(s)
Azepines/chemical synthesis , Cathepsins/antagonists & inhibitors , Cathepsins/chemistry , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Sulfones/chemical synthesis , Amides/chemistry , Azepines/chemistry , Binding Sites , Cathepsin L , Cysteine Proteinase Inhibitors/chemistry , Humans , Models, Molecular , Quinolines/chemistry , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Valine/analogs & derivatives , Administration, Oral , Animals , Dogs , Protease Inhibitors/chemical synthesis , Pyrrolidines/chemical synthesis , Rats , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacologyABSTRACT
Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.
