Herr H. Stein

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We have shown previously that the esters of adenosine-5'-carboxylic acid (10) represent a new class of potent nontoxic coronary vasodilators. For example, the ethyl ester (12), which is active by an intraduodenal or intravenous route in dogs, causes a large increase in coronary sinus PO2 and coronary blood flow. Because of the pronounced vasoactive(More)
Short-chain aliphatic esters and amides of adenosine-5'-carboxylic acid caused marked increases in coronary sinus oxygen tension (PO2) in the dog; the amides were generally more potent, causing additionally marked hypotension and tachycardia. The hypotensive effect was observed also in the spontaneously hypertensive rat. That the increase in coronary sinus(More)
A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent(More)
Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog,(More)
The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1,R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism(More)
A series of dipeptide analogues of angiotensinogen have been prepared and evaluated for their ability to inhibit the aspartic proteinase renin. The compounds were derived from the renin substrate by replacing the scissile amide bond with a transition-state mimic and by incorporating bioisosteric replacements for the Val-10 amide bond. Analogue 21a exhibited(More)
To establish whether the use of proteinase inhibitors in the routine determination of in vitro plasma renin activity overestimates the potency of renin inhibitors in vivo, we examined the effects of phenylmethylsulfonyl fluoride and 8-hydroxyquinoline sulfate on the binding to plasma proteins and the respective IC50 values (50% inhibiting concentrations) of(More)