ABSTRACT
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Subject(s)
Isoxazoles/chemistry , Naphthalenes/chemistry , Quinolines/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Binding Sites , Blood Glucose/metabolism , Crystallography, X-Ray , Diabetes Mellitus, Experimental/metabolism , Dogs , Fluorescence Resonance Energy Transfer , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Ligands , Mice , Molecular Conformation , Protein Structure, Tertiary , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Weight Gain/drug effectsABSTRACT
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Subject(s)
Isoxazoles/chemistry , Naphthalenes/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Thiophenes/chemistry , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Humans , Isoxazoles/pharmacology , Naphthalenes/pharmacokinetics , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship , Thiophenes/pharmacokineticsABSTRACT
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Subject(s)
Isoxazoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Crystallography, X-Ray , Fluorescence Resonance Energy Transfer , Isoxazoles/chemistry , Isoxazoles/pharmacology , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity RelationshipABSTRACT
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Cholestasis/drug therapy , DNA-Binding Proteins/agonists , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Administration, Oral , Animals , Carboxylic Acids/chemistry , Cholestasis/metabolism , Cholestasis/pathology , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , Disease Models, Animal , Dogs , Gastric Mucosa/metabolism , Haplorhini , Isoxazoles/chemistry , Mice , Molecular Conformation , Molecular Structure , Naphthalenes/chemistry , Rats , Receptors, Cytoplasmic and Nuclear/chemistry , Stomach/drug effects , Structure-Activity Relationship , Transcription Factors/chemistryABSTRACT
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
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Semicarbazones/pharmacology , Animals , Cathepsin K , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrogen-Ion Concentration , Hydrolysis , Models, Molecular , Molecular Conformation , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Semicarbazones/chemical synthesis , Semicarbazones/chemistry , Solubility , 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
Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.
Subject(s)
Cathepsins/antagonists & inhibitors , Cyanamide/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Osteogenesis/drug effects , Animals , Binding Sites , Bone Resorption , Cathepsin B/antagonists & inhibitors , Cathepsin H , Cathepsin K , Cathepsin L , Crystallography, X-Ray , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/chemical synthesis , Disease Models, Animal , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Binding , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.
Subject(s)
Amides/pharmacology , Cathepsins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Amides/chemical synthesis , Amides/pharmacokinetics , Binding Sites , Biological Availability , Cathepsin K , Cathepsins/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Kinetics , Protein Conformation , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition.
Subject(s)
Cathepsins/antagonists & inhibitors , Cyanamide/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Animals , Cathepsin K , Crystallography, X-Ray , Cyclization , Cysteine Proteinase Inhibitors/pharmacology , Inhibitory Concentration 50 , Pyrrolidines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.
Subject(s)
Aldehydes/chemistry , Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Aldehydes/pharmacology , Binding Sites/drug effects , Carbamates/chemistry , Cathepsin K , Humans , Inhibitory Concentration 50 , Norleucine/chemistry , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A novel series of ketoamide-based inhibitors of cathepsin K has been identified. Modifications to P(2) and P(3) elements were crucial to enhancing inhibitory activity. Although not optimized, a selected inhibitor was effective in attenuating type I collagen hydrolysis in a surrogate assay of bone resorption.
Subject(s)
Bone Resorption/metabolism , Bone and Bones/drug effects , Cathepsins/antagonists & inhibitors , Collagen Type I/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacology , Bone and Bones/pathology , Cathepsin K , Drug Design , Humans , Hydrolysis , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.
