Aliskiren hemifumarate

• Catalog No.: S2199
• CAS Number: 173334-58-2
• M. F.: C64H110N6O16
• M. W.: 1219.5888
• Storage: -20°C

SYNONYMS

• IUPAC name: (2E)-but-2-enedioic acid; bis((2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide)
• IUPAC Traditional name: fumaric acid; bis(tekturna)

DATABASE IDS

• CAS Number: 173334-58-2

PROPERTIES

• Target: Renin
• Salt Data: fumarate
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cardiovascular Disease

Biological Activity

• Description: Aliskiren hemifumarate is a direct renin inhibitor with IC50 of 1.5 nM.
• Targets: Renin
• IC50: 1.5 nM ^[1]
• In Vitro: 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: 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: Aliskiren hemifumarate is in Phase IV clinical trial of patients with hypertension.

Combination Therapy

• Description: 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

• Protocol: Kinase Assay ^[1]
• 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

• References: [1] Nakamura Y, et al. ACS Med Chem Lett, 2012, 3(9), 754–758.
• References: [2] Buczko W, et al. Pharmacol Rep, 2008, 60(5), 623-631.
• References: [3] Wood JM, et al. Biochem Biophys Res Commun, 2003, 308(4), 698-705.
• References: [4] Gradman AH, et al. Circulation, 2005, 111(8), 1012-1018.
• References: [5] Oparil S, et al. Lancet, 2007, 370(9583), 221-229.

REFERENCES

• Nakamura Y, et al. ACS Med Chem Lett, 2012, 3(9), 754–758.
• Buczko W, et al. Pharmacol Rep, 2008, 60(5), 623-631.
• Wood JM, et al. Biochem Biophys Res Commun, 2003, 308(4), 698-705.
• Gradman AH, et al. Circulation, 2005, 111(8), 1012-1018.
• Oparil S, et al. Lancet, 2007, 370(9583), 221-229.