Renin Inhibitors
Overview
Since the discovery in the early 1970s of a link between levels of renin and hypertension, investigators have postulated that modulating renin activity could be beneficial in hypertensive patients. In the early 1990s, these agents generated considerable interest, but by the mid 1990s, development began to wane as the early renin inhibitors proved to have poor bioavailability. Nevertheless, some compounds are still in development.
Speedel is investigating two series of renin inhibitors — SPP-500 and SPP-600 — under an exclusive license from Roche. In October 2002, the SPP-500 series was in late preclinical development. Pfizer also has an active development program for renin inhibitors, but all related work is in the discovery stage. Given the early stage of development, these compounds are not discussed further here.
Mechanism Of Action
Renin is a proteolytic enzyme produced by the kidneys in response to underperfusion or stimulation by the sympathetic nervous system. It catalyzes the conversion of plasma angiotensinogen to angiotensin I (AI). AI is in turn converted by angiotensin-converting enzyme (angiotensin-converting enzyme) to angiotensin II
All is a potent vasoconstrictive agent that also stimulates aldosterone secretion by the kidneys. Both of these actions increase blood volume, peripheral resistance, and cardiac output, which lead to the development of hypertension.
Renin inhibitors act upstream of current therapies, such as ACEIs and AIIRAs, in that they inhibit the conversion of angiotensinogen to AI and hence reduce the downstream effects of AIL
Aliskiren
The renin inhibitor in the most advanced stage of development is aliskiren (SP-100; formerly CGP-60536). Originally developed by Novartis and licensed to Speedel, aliskiren is a phenyloctane carboxamide and a nonpeptidic, orally active inhibitor of renin. Novartis opted to call back aliskiren following the completion of Phase II trials in 2002. The agent is now in Phase III trials in Europe, and Novartis anticipates filing an NDA in the United States in the first quarter of 2006, with a European filing anticipated later in the year.
A Phase I study in healthy volunteers showed that once-daily aliskiren inhibited AI and All in a dose-dependent manner. The inhibitory effects of aliskiren (160 mg) on the renin-angiotensin-aldosterone system were equivalent to the effects of 20 mg enalapril. These studies proved that aliskiren had favorable pharmacodynamics and sufficient oral bioavailability to affect the renin-angiotensin-aldosterone system.
In a small Phase Ha trial of aliskiren involving patients with mild-to-moderate hypertension, researchers observed a dose-dependent reduction in blood pressure (blood pressure) during the eight-week study period. In a Phase II, multicen-ter, randomized, double-blind trial involving 226 patients with mild-to-moderate hypertension, aliskiren (75, 100, and 300 mg) caused a dose-dependent reduction in systolic blood pressure, diastolic blood pressure, and ambulatory blood pressure in both daytime and nighttime readings. The study’s primary end point was the effect of aliskiren on daytime systolic blood pressure; responses observed were of magnitudes similar to those recorded for losartan (100 mg). Aliskiren was safe and well tolerated; its safety profile was similar to that of losartan.
In another Phase lib study involving 650 hypertensive patients, eight weeks’ treatment with aliskiren resulted in dose-dependent declines in both diastolic blood pressure and systolic blood pressure. The study found that 150 mg aliskiren was equivalent to 150 mg irbesartan, while higher doses of aliskiren (300 and 600 mg) were superior to irbesartan (150 mg) in lowering diastolic blood pressure.
Another Phase lib study is ongoing. The aim of this study is to compare the effects of aliskiren and valsartan combination therapy with monotherapy. Novartis claims that “[aliskiren] may offer synergistic blood pressure-lowering activity with Diovan (valsartan) in addition to protecting against organ (kidney) damage”.
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