ABSTRACT
Structure-activity relationship (SAR) studies of novel 5-alkyl and 5-aryl/heteroaryl substituted 1,2,4-triazoles are described. The in vitro activity is compared to the pyrazole class of compounds with analogous side chains to delineate the contribution of the triazole ring nitrogen in binding to the active site. Both series are quite potent and selective in the canine whole blood (CWB) COX-2 assay, suggesting the increased binding contribution of the hydrophobic side chains.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Ethers/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Alkylation , Animals , Cyclooxygenase 2 Inhibitors/blood , Cyclooxygenase 2 Inhibitors/chemistry , Dogs , Inhibitory Concentration 50 , Molecular Structure , Pyrazoles/blood , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfhydryl Compounds/blood , Sulfhydryl Compounds/chemistry , Triazoles/blood , Triazoles/chemistryABSTRACT
The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.
Subject(s)
Carbamates/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Indoles/chemical synthesis , Obesity/drug therapy , Animals , Carbamates/chemistry , Carbamates/pharmacology , Carboxylic Acids/pharmacology , Dogs , Drug Design , Drug Evaluation, Preclinical , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , RatsABSTRACT
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Nitriles/chemistry , Nitriles/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Animals , Binding Sites/drug effects , Celecoxib , Cyclooxygenase 1/metabolism , Dogs , Drug Design , Humans , Hydrogen Bonding , In Vitro Techniques , Indicators and Reagents , Kinetics , Models, Molecular , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Carrier Proteins/antagonists & inhibitors , Administration, Oral , Animals , Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/chemistry , Carrier Proteins/metabolism , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Dogs , Inhibitory Concentration 50 , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Ethers/chemistry , Pyrazoles/chemistry , Sulfhydryl Compounds/chemistry , Alkylation , Animals , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Dogs , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.
Subject(s)
Cyclooxygenase 2 Inhibitors , Cyclooxygenase 2/drug effects , Pyrazoles , Administration, Oral , Animals , Cats , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , In Vitro Techniques , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model.
Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Prostaglandin-Endoperoxide Synthases/drug effects , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Dogs , In Vitro Techniques , Magnetic Resonance Spectroscopy , Pyrazoles/chemical synthesis , Pyridines/chemical synthesisABSTRACT
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.
