C. Anne Higley

MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products.

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.

Pyrazoles, 1,2,4-triazoles, and tetrazoles as surrogates for cis-amide bonds in boronate ester thrombin inhibitors.

Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.

Acyl CoA:cholesterol acyltransferase (ACAT) inhibitors: ureas bearing heterocyclic groups bioisosteric for an imidazole

Abstract A series of compounds bearing heterocyclic substituents were prepared, and evaluated for inhibition of the ACAT enzyme. The heterocyclic groups were compared in terms of in vitro potency against their diarylimidazole analogues. Data for the purposes of QSAR were also collected. Our goal is a systemic ACAT inhibitor, which would be a potential antihypercholesterolemic and antiatherosclerotic agent.