ABSTRACT
Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Subject(s)
Nitrogen/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Biological Availability , Half-Life , Phosphodiesterase Inhibitors/pharmacokinetics , Quinolines/pharmacokinetics , Rats , SaimiriABSTRACT
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Bronchoconstriction/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Guinea Pigs , Humans , Inhibitory Concentration 50 , Phosphodiesterase Inhibitors/toxicity , Quinolines/toxicity , Rats , Saimiri , Sheep , Structure-Activity Relationship , Vomiting/chemically inducedABSTRACT
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.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacokinetics , Isoenzymes/antagonists & inhibitors , Pyridazines/chemical synthesis , Animals , Cell Line , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Edema/drug therapy , Humans , Inhibitory Concentration 50 , Membrane Proteins , Metabolic Clearance Rate , Prostaglandin-Endoperoxide Synthases , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.