ABSTRACT
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.
