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); but-2-enedioic acid

• ChemBase编号: 72892
• 分子式: C64H110N6O16
• 平均质量: 1219.5888
• 单一同位素质量: 1218.79783147
• SMILES: c1(c(cc(cc1)C[C@@H](C[C@@H]([C@H](C[C@H](C(=O)NCC(C(=O)N)(C)C)C(C)C)O)N)C(C)C)OCCCOC)OC.c1(c(cc(cc1)C[C@@H](C[C@@H]([C@H](C[C@H](C(=O)NCC(C(=O)N)(C)C)C(C)C)O)N)C(C)C)OCCCOC)OC.C(=O)(/C=C/C(=O)O)O
• Canonical SMILES: OC(=O)/C=C/C(=O)O.COCCCOc1cc(ccc1OC)C[C@H](C(C)C)C[C@@H]([C@H](C[C@H](C(=O)NCC(C(=O)N)(C)C)C(C)C)O)N.COCCCOc1cc(ccc1OC)C[C@H](C(C)C)C[C@@H]([C@H](C[C@H](C(=O)NCC(C(=O)N)(C)C)C(C)C)O)N
• InChI: InChI=1S/2C30H53N3O6.C4H4O4/c2*1-19(2)22(14-21-10-11-26(38-8)27(15-21)39-13-9-12-37-7)16-24(31)25(34)17-23(20(3)4)28(35)33-18-30(5,6)29(32)36;5-3(6)1-2-4(7)8/h2*10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35);1-2H,(H,5,6)(H,7,8)/b;;2-1+/t2*22-,23-,24-,25-;/m00./s1
• InChIKey: KLRSDBSKUSSCGU-KRQUFFFQSA-N

名称和登记号

名称

• IUPAC标准名: 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); but-2-enedioic acid; (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传统名: bis(aliskiren); butenedioic acid; fumaric acid; bis(tekturna)
• 别名: 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); but-2-enedioic acid; Aliskiren hemifumarate

登记号

• CAS号: 173334-58-2
• MDL号: MFCD10566724
• PubChem SID: 162037813
• PubChem CID: 6918427

理论计算性质

• Acid pKa: 14.557217
• 质子受体: 7
• 质子供体: 4
• LogD (pH = 5.5): 0.12925176
• LogD (pH = 7.4): 1.0046214
• Log P: 3.1245122
• 摩尔折射率: 154.3183 cm^3
• 极化性: 61.064808 Å^3
• 极化表面积: 146.13 Å^2
• 可自由旋转的化学键: 40
• 里宾斯基五规则: false

分子性质

理化性质

• 疏水性(logP): 3.514

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: Renin

产品相关信息

• 纯度: 95%
• 成盐信息: fumarate

详细说明

Selleck Chemicals - S2199

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.

参考文献

• 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.