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
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.
