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Aliskiren hemifumarate (CGP-60536; CGP60536; Rasilez; SPP100; SPP-100; Tekturna), the hemifumarate salt form of Aliskiren, is a potent and direct renin inhibitor with antihypertensive activity. It inhibits renin with an IC50 of 1.5 nM. Aliskiren is the first-in-class drugs called direct renin inhibitors approved for use in the treatment of essential (primary) hypertension. 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.
Physicochemical Properties
| Molecular Formula | C30H53N3O6.1/2C4H4O4 | |
| Molecular Weight | 609.83 | |
| Exact Mass | 1218.8 | |
| CAS # | 173334-58-2 | |
| Related CAS # | Aliskiren;173334-57-1;Aliskiren hydrochloride;173399-03-6;Aliskiren-d6 hydrochloride;1246815-96-2;Aliskiren-d6 hemifumarate | |
| PubChem CID | 6918427 | |
| Appearance | White to off-white solid powder | |
| Melting Point | 72-75?C | |
| Vapour Pressure | 1.59E-23mmHg at 25°C | |
| LogP | 9.881 | |
| Hydrogen Bond Donor Count | 10 | |
| Hydrogen Bond Acceptor Count | 18 | |
| Rotatable Bond Count | 40 | |
| Heavy Atom Count | 86 | |
| Complexity | 836 | |
| Defined Atom Stereocenter Count | 8 | |
| SMILES | CC(C)[C@@H](CC1=CC(=C(C=C1)OC)OCCCOC)C[C@@H]([C@H](C[C@@H](C(C)C)C(=O)NCC(C)(C)C(=O)N)O)N.CC(C)[C@@H](CC1=CC(=C(C=C1)OC)OCCCOC)C[C@@H]([C@H](C[C@@H](C(C)C)C(=O)NCC(C)(C)C(=O)N)O)N.C(=C/C(=O)O)\C(=O)O |
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| InChi Key | KLRSDBSKUSSCGU-KRQUFFFQSA-N | |
| InChi Code | 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) | |
| Chemical Name | (αS,γS,δS,ζS)-δ-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-γ-hydroxy-4-methoxy-3-(3-methoxypropoxy)-α,ζ-bis(1-methylethyl)-benzeneoctanamide, 2E-butenedioate | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | The in vitro inhibition of plasma renin activity (PRA) by isoskiren hemifumarate has IC50 values of 2.9 nM for human PRA and 8.0 nM for monkey PRA, respectively[1]. Human aortic smooth muscle cell migration induced by prorenin is inhibited by isoformisin hemifumarate (5 μM; 24 h)[2]. Aliskiren hemifumarate (1–10 μM; 24 h) significantly reduces prorenin-induced morphological alterations and lamellipodia development while having no effect on PDGF-BB activity[2]. |
| ln Vivo | In marmosets with low sodium levels, isoproterenol (3 mg/kg, 10 mg/kg; po; daily; 0–12 d) inhibits renin and lowers blood pressure without altering heart rate[3]. Aliskiren hemifumarate (10 mg/kg; po; single dose) decreases tumor size, postpones the onset of cachexia, and increases the survival time of mice. Additionally, it increases locomotor activity, prevents muscular atrophy, and improves strength, mobility, and coordination throughout the entire body[4]. 20 days after C26 injection, a single dose of 10 mg/kg of aliskiren hemifumarate is administered po to alleviate oxidative stress linked to cancer cachexia[4]. |
| Cell Assay |
Cell Viability Assay[2] Cell Types: Smooth muscle cell (SMC) Tested Concentrations: 1-10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Inhibited human aortic smooth muscle cell migration induced by prorenin (10 nM) at 10 μM. |
| Animal Protocol |
Animal/Disease Models: Sodium-depleted marmosets[3] Doses: 3 mg/kg, 10 mg/kg Route of Administration: po (oral gavage); one time/day; 12 days Experimental Results: Increased plasma immunoreactive renin levels, and lowered blood pressure without affecting heart rate. demonstrated no rebound increase in BP following the end of treatment with either dose of aliskiren. Inhibited the RAS and controls the upregulation of pro‑inflammatory cytokines. Animal/Disease Models: Cancer cachexia model in balb/c (Bagg ALBino) mouse injected with C26 mouse colon carcinoma cells[4] Doses: 10 mg/kg Route of Administration: po (oral gavage); on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection; for 20 days after C26 injection Experimental Results: Enhanced grip strength, coordination, and locomotor activity. Inhibited serum Ang I and Ⅱ levels and both serum and muscular tumor necrosis factor‑α (TNF‑α) and inter‑ leukin‑6 (IL‑6) levels. |
| References |
[1]. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor. ACS Med. Chem. Lett., 2012, 3 (9), pp 754-758. [2]. Aliskiren inhibits prorenin-induced human aortic smooth muscle cell migration. J Renin Angiotensin Aldosterone Syst. 2015 Jun;16(2):284-91. [3]. Structure-based design of aliskiren, a novel orally effective renin inhibitor.Biochem Biophys Res Commun, 2003, 308(4), 698-705. [4]. Aliskiren targets multiple systems to alleviate cancer cachexia. Oncol Rep. 2016 Nov;36(5):3014-3022. [5]. Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. Pharmacol Rep. 2008 Sep-Oct;60(5):623-31. [6]. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation, 2005, 111(8), 1012-1018. |
| Additional Infomation |
Aliskiren fumarate is the hemifumarate salt of aliskiren. It has a role as an antihypertensive agent. It contains an aliskiren. Aliskiren Hemifumarate is an orally active nonpeptide renin inhibitor with antihypertensive activity. Aliskiren selectively binds to the S3 sub-pocket of renin, an enzyme in the renin-angiotensin-aldosterone system (RAAS) that is responsible for converting angiotensinogen to angiotensin I (AT I). By inhibiting the activity of renin, the conversion to AT I is prevented, which in turn prevents the conversion of AT I to AT II. This prevents arterial vasoconstriction by AT II and inhibits the production of aldosterone by AT II. As aldosterone causes re-uptake of sodium and water and eventually an increase in extracellular volume, aliskiren is able to prevent the effects that contribute to an increase in blood pressure. See also: Aliskiren (has active moiety); Aliskiren hemifumarate; amlodipine besylate (component of); Aliskiren hemifumarate; hydrochlorothiazide (component of) ... View More ... |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (41.00 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6398 mL | 8.1990 mL | 16.3980 mL | |
| 5 mM | 0.3280 mL | 1.6398 mL | 3.2796 mL | |
| 10 mM | 0.1640 mL | 0.8199 mL | 1.6398 mL |