ABSTRACT
In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.
Subject(s)
Butadienes/chemistry , Enzyme Inhibitors/chemistry , Nitriles/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Biotransformation , Butadienes/pharmacokinetics , Butadienes/pharmacology , Cyclization , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , NF-kappa B/antagonists & inhibitors , Nitriles/pharmacokinetics , Nitriles/pharmacology , Rats , Transcription Factor AP-1/antagonists & inhibitorsABSTRACT
Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.
Subject(s)
Amides/pharmacology , Boronic Acids/pharmacology , Pyrazoles/pharmacology , Tetrazoles/pharmacology , Thrombin/antagonists & inhibitors , Thrombin/chemistry , Triazoles/pharmacology , Amides/chemistry , Binding Sites , Boronic Acids/chemistry , Crystallography, X-Ray , Indicators and Reagents , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Stereoisomerism , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions alpha and beta to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.
Subject(s)
Isoxazoles/chemistry , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Administration, Oral , Animals , Blood Platelets/drug effects , Dogs , Drug Design , Female , Isoxazoles/administration & dosage , Isoxazoles/pharmacology , Macaca mulatta , Male , Models, Chemical , Papio , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacologyABSTRACT
Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the development of fatty streaks. Inhibitors of the ACAT enzyme may retard this atherogenic process. We have recently discovered a series of imidazoles which are potent in vitro ACAT inhibitors in the J774 macrophage cell culture assay. This paper will describe the design, synthesis, and structure--activity relationship for this very potent series of compounds.
Subject(s)
Macrophages/enzymology , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Cell Line , Drug Design , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Isoenzymes/antagonists & inhibitors , Mice , Microsomes, Liver/enzymology , Rats , Structure-Activity RelationshipABSTRACT
A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.
