ABSTRACT
The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
Subject(s)
Cathepsin K/antagonists & inhibitors , Ethylamines/chemistry , Protease Inhibitors/chemistry , Administration, Oral , Amides/chemistry , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Cathepsin K/metabolism , Dogs , Ethylamines/chemical synthesis , Ethylamines/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , RatsABSTRACT
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.
Subject(s)
Biphenyl Compounds/administration & dosage , Biphenyl Compounds/pharmacokinetics , Cathepsin K/antagonists & inhibitors , Cysteine Proteinase Inhibitors/administration & dosage , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Discovery/methods , Administration, Oral , Animals , Biological Availability , Biphenyl Compounds/chemistry , Cathepsin K/metabolism , Cysteine Proteinase Inhibitors/chemistry , Dogs , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Macaca mulatta , Rabbits , RatsABSTRACT
A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.
Subject(s)
Hydrocarbons, Halogenated/chemical synthesis , Hydrocarbons, Halogenated/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Animals , Combinatorial Chemistry Techniques , Diabetes Mellitus/chemically induced , Disease Models, Animal , Drug Design , Drug Screening Assays, Antitumor , Haplorhini , Hydrocarbons, Halogenated/chemistry , Mice , Molecular Structure , Naphthalenes/chemistry , Neoplasms/chemically induced , Organophosphonates/chemistry , RatsABSTRACT
The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.
Subject(s)
Arginine/analogs & derivatives , Benzhydryl Compounds/pharmacology , Calcium/metabolism , Membrane Proteins/agonists , Receptors, Complement/agonists , Animals , Arginine/pharmacology , Binding, Competitive , Blood Platelets/drug effects , Blood Platelets/metabolism , CHO Cells , Cell Line, Tumor , Cell Membrane/drug effects , Cell Membrane/metabolism , Complement C3a , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Humans , Macaca fascicularis , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Rats , Receptors, Complement/antagonists & inhibitors , Receptors, Complement/genetics , Transfection , U937 Cells , beta-Lactamases/genetics , beta-Lactamases/metabolismABSTRACT
The synthesis of a novel radioactive peptidic photoaffinity probe for the PTP-1B enzyme as well as some SAR leading to the choice of this compound as a photoaffinity probe are presented.
Subject(s)
Photoaffinity Labels/chemical synthesis , Protein Tyrosine Phosphatases/chemistry , Photoaffinity Labels/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1ABSTRACT
A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Animals , Cell Line , Cell Survival/drug effects , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Insecta , Mice , Mice, Knockout , Models, Molecular , Molecular Structure , Organophosphorus Compounds/chemical synthesis , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Structure-Activity RelationshipABSTRACT
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
Subject(s)
Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Triazoles/chemistry , Triazoles/pharmacology , Amino Acids/genetics , Amino Acids/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Phosphinic Acids/chemistry , Phosphinic Acids/metabolism , Phosphinic Acids/pharmacology , Point Mutation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.