A new class of orally active glycol renin inhibitors containing phenyllactic acid at P3

Hanson, Gunnar J.; Baran, John S.; Lowrie, Harman S.; Russell, Mark A.; Sarussi, Steven J.; Williams, Kenneth; Babler, Maribeth; Bittner, Stephen E.; Papaioannou, Spyros; Yang, Po-Chang; Walsh, Gerald M.

doi:10.1016/0006-291x(89)91611-2

Cited by 19 publications

(1 citation statement)

References 9 publications

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“…These inhibitors are CGP-29287 (36), U-71038 (28), SR-43845 (26), Compound 12 (l), A-64662 (19). SC-46944 (8), KRI (21), CGP-38560 (35), and BW-175 (23). However, because of their low bioavailability, the doses of more than 10 mg/kg were required to cause a significant decrease in PRA by oral administration.…”

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An Orally Active Inhibitor of Human Renin, ES‐8891

Kokubu

Hiwada

Murakami

et al. 1991

Cardiovascular Drug Reviews

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Key Words: Human renin inhibitor-Marmoset-Human-Bloodpressure-Plasma renin activity-Renin mRNA.The renin-angiotensin system plays an important role in the regulation of blood pressure and in body fluid homeostasis. Inhibitors of angiotensin converting enzyme (ACE) are now widely used in patients with hypertension and congestive heart failure. The success of ACE inhibitors in the treatment of hypertension has stimulated the development of specific inhibitors of human renin. Renin inhibitors are expected to produce more selective inhibition of the renin-angiotensin system than ACE inhibitors. Since ACE converts angiotensin I (AngI) to Ang I1 and also inactivates bradykinin, enkephalins, and other biologically active peptides (30), ACE inhibitors are not specific blockers of the renin-angiotensin system. Renin acts on angiotensinogen as its only known substrate (29). Thus, renin inhibitors may have a lower incidence of adverse effects, typical for ACE inhibitors, such as flushing, dry cough, or angioedema, which may be independent of the renin-angiotensin system. Cough induced by ACE inhibitors has been suspected to be caused by the increase in bradykinin or substance P (22). Furthermore, the inhibition of the renin-angiotensin system by renin inhibitors may also contribute to our understanding of the role of the renin-angiotensin system in cardiovascular homeostasis.Hemodynamic and biochemical consequence of renin inhibition have been studied following parenteral administration. The renin inhibitors CGP-38560A (5,27) and enalkiren (6) caused no change of blood pressure in spite of renin inhibition in normotensive subjects on standard sodium diet. However, the infusion of the renin inhibitor H-142 lowered blood pressure when normal subjects were sodium depleted (33,34). In contrast, the renin inhibitors CGP-38560A (27), enalkiren (6), and A-64662 (2) significantly reduced the blood pressure in hypertensive patients on normal sodium diet without any Address correspondence and reprint requests to Prof. K.

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