ABSTRACT
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Subject(s)
Pteridines/chemistry , Pyrazines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Half-Life , Pteridines/chemical synthesis , Pteridines/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity RelationshipABSTRACT
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , 5-Lipoxygenase-Activating Proteins/chemistry , Alkanes/chemical synthesis , Anti-Allergic Agents/chemical synthesis , Benzene Derivatives/chemical synthesis , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacokinetics , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacology , 5-Lipoxygenase-Activating Proteins/metabolism , Alkanes/pharmacokinetics , Alkanes/pharmacology , Animals , Anti-Allergic Agents/pharmacokinetics , Anti-Allergic Agents/pharmacology , Benzene Derivatives/pharmacokinetics , Benzene Derivatives/pharmacology , Humans , Inhibitory Concentration 50 , Injections, Intravenous , Neutrophils/drug effects , Neutrophils/metabolism , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.