Research Area
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Description
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Cardiovascular Disease |
Biological Activity
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Description
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Aliskiren hemifumarate is a direct renin inhibitor with IC50 of 1.5 nM. |
Targets
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Renin |
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IC50 |
1.5 nM [1] |
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In Vitro
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Aliskiren hemifumarate appears to bind to both the hydrophobic S1/S3-binding pocket and to a large, distinct subpocket that extends from the S3-binding site towards the hydrophobic core of renin. Oral bioavailability of Aliskiren hemifumarate is 2.4% in rats, 16% in marmosets and about 2.5% in humans. [2] |
In Vivo
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Aliskiren hemifumarate (< 10="" mg/kg,="" oral)="" inhibits="" plasma="" renin="" activity="" and="" lowers="" blood="" pressure="" in="" sodium-depleted="" marmosets.="">[3] Once-daily oral treatment with Aliskiren hemifumarate lowers blood pressure effectively, with a safety and tolerability profile, in patients with mild-to-moderate hypertension. [4] |
Clinical Trials
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Aliskiren hemifumarate is in Phase IV clinical trial of patients with hypertension. |
Features
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Combination Therapy
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Description
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The combination of Aliskiren hemifumarate (300 mg) and Valsartan (320 mg) lower mean sitting diastolic blood pressure from baseline by 12? mm Hg, significantly more than either monotherapy. [5] |
Protocol
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Kinase Assay
[1]
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Enzyme inhibition assay |
All reactions are carried out in a flat bottom black opaque microtiter plate. Aliskiren hemifumarate in DMSO (2 μL) are mixed with 100 μL of the assay buffer (50 mM Tris-HCl (pH7.9), 100 mM NaCl) containing 5 μL of trypsin-activated recombinant human renin (final enzyme concentration of 50 μM), and the solution is pre-incubated at room temperature for 10 min. Next, 2 μM of the substrate (Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg) in 100 μL of the assay buffer is added, and the resulting mixture is incubated at 37 °C for 90 min. After completion of incubation, the concentration of generated angiotensin I is measured by fluorescence at 492 nm (excitation at 340 nm) using a multilabel reader. |
References |
[1] Nakamura Y, et al. ACS Med Chem Lett, 2012, 3(9), 754–758.
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[2] Buczko W, et al. Pharmacol Rep, 2008, 60(5), 623-631.
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[3] Wood JM, et al. Biochem Biophys Res Commun, 2003, 308(4), 698-705.
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[4] Gradman AH, et al. Circulation, 2005, 111(8), 1012-1018.
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[5] Oparil S, et al. Lancet, 2007, 370(9583), 221-229.
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