John V. Duncia

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.

Biaryl substituted alkylboronate esters as thrombin inhibitors

Abstract Thrombin is a serine protease that plays an important role in the blood coagulation cascade, and is a target enzyme for new therapeutic agents. Ac-(D)-Phe-Pro-boroArg-OH (DuP 714) was found to be a highly effective thrombin inhibitor. In order to reduce the peptidic nature of DuP 714, we have designed a series of novel biaryl substituted alkylboronate esters as potent thrombin inhibitors. The most potent compounds have subnanomolar affinity for thrombin.

BALANCED ANGIOTENSIN II RECEPTOR ANTAGONISTS. III: THE EFFECTS OF SUBSTITUTION AT THE IMIDAZOLE 5-POSITION

Abstract We wish to report on a series of substituted methyl esters and amides of DMP 811, which bind to both the AT 1 and AT 2 receptor subtypes. Some of the esters bind well to both receptor subtypes in the subnanomolar range when the optimal acid isostere is present together with an ortho-fluorine substituent on the biphenylmethyl group.

EXP597, a nonpeptide angiotensin II receptor antagonist with high affinities for the angiotensin AT1 and AT2 receptor subtypes

AT1 and AT2 are the two major receptor subtypes for angiotensin II that have been pharmacologically defined by using the selective ligands losartan and PD123177, respectively. EXP597 (4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazole-1- yl)methyl]-3-fluoro-2-isoamyloxycarbonylaminosulfonyl-[1,1]-biph enyl, potassium salt) is a nonpeptide angiotensin II receptor ligand which in the rat adrenal exhibits binding affinities (IC50) of 0.5 and 0.7 nM for angiotensin AT1 and AT2 receptor subtypes, respectively. Further, EXP597 is an insurmountable angiotensin II receptor antagonist in the isolated rabbit aorta and lowers blood pressure in renal hypertensive rats with i.v. and p.o. ED30 values of 0.05 and 0.9 mg/kg, respectively.

Dibenzobicyclo[2.2.2.]octane angiotensin II receptor antagonists

Abstract Most angiotensin II antagonists in the literature contain the biphenyltetrazole moiety. We now wish to report a new, more rigidized biphenyl replacement, namely the dibenzobicyclo[2.2.2.]octane scaffold. It was designed on the basis of the three-dimensional conformation of the biphenyltetrazole moiety of losartan, the prototypic angiotensin II antagonist. This biphenyltetrazole replacement fixes both the imidazole and the negatively charged (at physiological pH) tetrazole in the same areas of space where they are located in losartan. Other scaffolds such as a fluorene and Rebeks Cleft are also discussed.