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
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.
Subject(s)
Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/chemistry , Isoenzymes/antagonists & inhibitors , Pyridines/administration & dosage , Pyridines/chemistry , Administration, Oral , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Dogs , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Structure-Activity RelationshipABSTRACT
Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogues were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/pharmacology , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Animals , Cattle , Cattle Diseases/microbiology , Female , Gonadotropin-Releasing Hormone/chemical synthesis , Mastitis, Bovine/microbiology , Mice , Microbial Sensitivity Tests , Pasteurella multocida/drug effects , Pasteurellosis, Pneumonic/microbiology , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The aromatic derivatives of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-positive and Gram-negative bacteria.
