John V Duncia

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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,(More)
We have demonstrated the existence of two distinct subtypes of the angiotensin II receptor in the rat adrenal gland using radioligand binding and tissue section autoradiography. The identification of the subtypes was made possible by the discovery of two structurally dissimilar, nonpeptide compounds, DuP 753 and EXP655, that show reciprocal selectivity for(More)
A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect(More)
In the spinal pithed rat, DuP 753, 2-n-butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl) methyl] imidazole potassium salt, inhibited competitively the pressor response to angiotensin II (AII), whereas saralasin showed a noncompetitive pattern of interaction. It did not alter the pressor responses to vasopressin and norepinephrine as(More)
This report describes the pharmacology of (2-n-butyl-4-chloro-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid (EXP3174). EXP3174 is a major metabolite generated after the oral dosing of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt in rats. It displaced [3H]angiotensin(More)
A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor. Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II. The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII(More)
In conscious 18-21-week-old spontaneously hypertensive rats, DuP 753, a nonpeptide angiotensin II receptor antagonist, given orally at 3 and 10 mg/kg or intravenously at 3, 10, and 30 mg/kg, reduced blood pressure dose dependently. It did not alter heart rate at these doses. At 10 mg/kg i.v., DuP 753 decreased blood pressure significantly for at least 24(More)
Two types of angiotensin II (AII) receptor (AII-1 and AII-2) have been identified in rat adrenal cortex by means of two highly specific, but structurally dissimilar, nonpeptide AII receptor antagonists, DuP753 and EXP655, and by the discriminatory effect of dithiothreitol (DTT). Using radioligand-receptor binding techniques, DuP753 was found to be highly(More)
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(More)