Thomas L. Waldron

Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats

Endothelin is a potent pressor agent mediated primarily through activation of endothelin-A receptors on vascular smooth muscle. Surprisingly, there is no consensus in the literature regarding the role of endothelin itself or endothelin-A receptors in hypertension. The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hypertension. BMS-182874 specifically inhibited the pressor response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED25 = 8 mumol/kg IV) but had no effect on changes in mean arterial pressure brought about by other vasoactive agents. The antihypertensive effects of BMS-182874 were evaluated in conscious deoxycorticosterone acetate (DOCA)--salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DOCA--salt hypertensive rats when administered at a dose of 30, 100, or 300 mumol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 mumol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 mumol/kg) elicited a sustained decrease in blood pressure in the DOCA--salt hypertensive rats. In SHR, BMS-182874 decreased blood pressure by approximately 30 mm Hg, but the antihypertensive effects were similar at doses of 75, 150, and 450 mumol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally active endothelin-A receptor antagonist that is efficacious in mineralocorticoid hypertension in rats but has less effect in sodium-replete and sodium-deplete SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

MERCAPTOACYL DIPEPTIDES AS DUAL INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE PRELIMINARY STRUCTURE-ACTIVITY STUDIES

Abstract Mercaptoacyl dipeptides were prepared as dual-acting ACE/NEP inhibitors. Inhibition of each enzyme may be explained by different binding models. Structure-activity studies determined that, in this series of compounds, the mercaptopropanoyl dipeptide framework leads to increased affinity for NEP but diminished ACE activity in vivo .

The effects of novel cathepsin E inhibitors on the big endothelin pressor response in conscious rats

The aspartic protease, cathepsin E, has been shown to specifically cleave big endothelin (big ET-1) at the Trp21-Val22 bond to produce endothelin (ET-1) and the corresponding C-terminal fragment. To determine whether cathepsin E is a physiologically relevant endothelin converting enzyme (ECE), three novel and potent inhibitors of cathepsin E were administered to conscious rats prior to a pressor challenge with big ET-1. One of the inhibitors of cathepsin E, SQ 32,056 (3 mg/kg i.v.), blocked the big ET-1 response. However, this dose of SQ 32,056 also blocked the pressor response to ET-1. Phosphoramidon specifically inhibited the Big ET-1 pressor response. These results suggest that ECE is not cathepsin E.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: A potent and selective full agonist of the human β3 adrenergic receptor

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

Quantitation of tremor in response to β-adrenergic receptor stimulation in primates: relationship with hypokalemia

The primary adverse effect of stimulation of beta2-adrenergic receptors is elicitation of tremor. Tremor measurements in response to beta2-adrenergic receptor stimulation were performed in a quantitative manner using a modified miniature semiconductor accelerometer in African green monkeys. The accelerometer was taped to the middle finger tip of anesthetized monkeys, and recordings of onset, duration and peak tremor responses were obtained. The selective beta2-adrenergic agonist, salbutamol (0.5 mg/kg i.v.), caused a marked increase in tremor which started within 5 min following injection and lasted for approximately 60 min. The finger tremor response was not visible, but was measurable by the accelerometer, and the increase in tremor was significantly greater from baseline within 10 min. Plasma K+ concentrations were markedly decreased within the first 15 min and remained at low steady-state concentrations during the 60-min recordings. The tremor response was abolished by the selective beta2-adrenergic receptor antagonist, ICI-118551 (0.2 mg/kg). ICI-118551 caused a significant reversal of the plasma K+ decrease but the K+ levels remained higher than control levels. These studies demonstrate that stimulation of beta2-adrenergic receptors causes tremor, most likely from entry of K+ into skeletal muscle and that there is a direct correlation between tremor and hypokalemic response.

Synthesis, biological properties, and structure-activity relationships of quinoxaline angiotensin II receptor antagonists

Abstract Quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. All five analogs reported here display potent antagonistic activities and most interestingly, quinozaline bis-N-oxide 10 exhibits very potent activities both in binding and functional assays.

1,4-substituted indoles: a potent and selective class of angiostensin II receptor antagonists

The syntheses and pharmacological activity of a series of 1,4-substituted indoles which function as nonpeptidic antagonists of the angiotensin II (AII) receptor are described. Compounds in this series are orally active and demonstrate long lasting antihypertensive activity.

Quinoline-4-carboxylic acids as angiotensin II receptor antagonists

Abstract We have synthesized a series of quinoline-4-carboxylic acids that are potent antagonists of the angiotensin II receptor. They show high receptor binding affinities and functional antagonism in rabbit aortic strips. They are also effective in blocking the hypertensive effects of AII in vivo

Diol sulfonamides: A potent and novel class of inhibitors of human renin

Abstract The syntheses and pharmacological activity of a series of diol sulfonamides which function as inhibitors of human renin are described. The most potent compound in this series, compound 20 (SQ 33,800 ), is a subnanomolar inhibitor of human renin (IC 50 = 0.35 × 10 −9 M).