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Identification
NameAliskiren
Accession NumberDB09026  (DB01258)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Aliskiren is the first in a class of drugs called direct renin inhibitors. Its current licensed indication is essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit. In December 2011, Novartis halted a clinical trial of the drug after discovering increased incidence of nonfatal stroke, kidney complications, high blood potassium, and low blood pressure in people with diabetes and kidney impairment.

Structure
Thumb
SynonymsNot Available
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Rasileztablet300 mgoralNovartis Pharmaceuticals Canada Inc2007-11-29Not applicableCanada
Rasileztablet150 mgoralNovartis Pharmaceuticals Canada Inc2007-11-26Not applicableCanada
Sandoz Aliskirentablet150 mgoralSandoz Canada IncorporatedNot applicableNot applicableCanada
Sandoz Aliskirentablet300 mgoralSandoz Canada IncorporatedNot applicableNot applicableCanada
Tekturnatablet, film coated150 mg/1oralNovartis Pharmaceuticals Corporation2007-03-05Not applicableUs
Tekturnatablet, film coated300 mg/1oralPhysicians Total Care, Inc.2009-06-22Not applicableUs
Tekturnatablet, film coated150 mg/1oralPhysicians Total Care, Inc.2007-05-23Not applicableUs
Tekturnatablet, film coated300 mg/1oralNovartis Pharmaceuticals Corporation2007-03-05Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
AmturnideNovartis Pharmaceuticals Corporation
Rasilez HctNovartis Pharmaceuticals Canada Inc
TekamloNovartis Pharmaceuticals Corporation
Tekturna HctNovartis Pharmaceuticals Corporation
Salts
Name/CASStructureProperties
Aliskiren hemifumarate
ThumbNot applicableDBSALT001203
Categories
UNII502FWN4Q32
CAS number173334-57-1
WeightAverage: 551.7583
Monoisotopic: 551.393436443
Chemical FormulaC30H53N3O6
InChI KeyUXOWGYHJODZGMF-QORCZRPOSA-N
InChI
InChI=1S/C30H53N3O6/c1-19(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/h10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35)/t22-,23-,24-,25-/m0/s1
IUPAC Name
(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
SMILES
COCCCOC1=C(OC)C=CC(C[C@@H](C[[email protected]](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as delta amino acids and derivatives. These are compounds containing a carboxylic acid group and an amino group at the C5 carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentDelta amino acids and derivatives
Alternative Parents
Substituents
  • Delta amino acid or derivatives
  • Phenylbutylamine
  • Beta amino acid or derivatives
  • Methoxybenzene
  • Phenol ether
  • Anisole
  • Aralkylamine
  • Alkyl aryl ether
  • Fatty acyl
  • Benzenoid
  • N-acyl-amine
  • Fatty amide
  • Monocyclic benzene moiety
  • Secondary carboxylic acid amide
  • Secondary alcohol
  • Primary carboxylic acid amide
  • Carboxamide group
  • 1,2-aminoalcohol
  • Ether
  • Dialkyl ether
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of hypertension, to lower blood pressure.
PharmacodynamicsIn placebo controlled clinical trials, plasma renin activity (PRA) was decreased in a range of 50% to 80%. This reduction in PRA was not dose‐related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.
Mechanism of actionRenin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by ACE and non‐ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin‐angiotensin‐aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non‐ACE pathways, is not known. All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACEIs and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.
Related Articles
AbsorptionPoor, with a bioavailability of about 2.5%.
Volume of distributionNot Available
Protein binding47-51%
Metabolism

Approximately 80% of the drug in plasma following oral administration is unchanged. Cytochrome P450 (CYP) 3A4 oxidation produces two major metabolites that account for approximately 5% of the drug in plasma. Aliskiren is eliminated primarily through the biliary/fecal route as unchanged drug and, to a lesser extent, via oxidative metabolism via CYP3A4. Only 0.6% of the oral dose is recovered in urine.

Route of eliminationAbout one fourth of the absorbed dose appears in the urine as parent drug.
Half lifeApproximate accumulation half‐life of 24 hours.
ClearanceNot Available
ToxicityThe most likely manifestation of overdosage would be hypotension.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral150 mg
Tabletoral300 mg
Tabletoral
Tablet, film coatedoral150 mg/1
Tablet, film coatedoral300 mg/1
Tablet, film coatedoral
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2147056 No2005-10-252015-04-13Canada
US5559111 No1998-07-212018-07-21Us
US8168616 No2006-07-032026-07-03Us
US8183295 No2003-05-162023-05-16Us
US8613949 No2009-12-212029-12-21Us
US8617595 No2006-02-192026-02-19Us
US8618172 No2008-07-132028-07-13Us
US8618174 No2001-11-152021-11-15Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityHighly soluble in water (as hemifumarate salt)Not Available
logP3.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0021 mg/mLALOGPS
logP3.87ALOGPS
logP3.12ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)14.56ChemAxon
pKa (Strongest Basic)9.57ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area146.13 Å2ChemAxon
Rotatable Bond Count19ChemAxon
Refractivity154.32 m3·mol-1ChemAxon
Polarizability64.25 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP: Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515-31. [PubMed:18611061 ]
  2. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP: Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005 Mar 1;111(8):1012-8. Epub 2005 Feb 21. [PubMed:15723979 ]
  3. Staessen JA, Li Y, Richart T: Oral renin inhibitors. Lancet. 2006 Oct 21;368(9545):1449-56. [PubMed:17055947 ]
External Links
ATC CodesC09DX02C09XA02C09XA52C09XA53C09XA54
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (612 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Aliskiren.
AlfuzosinAlfuzosin may increase the hypotensive activities of Aliskiren.
AmifostineAliskiren may increase the hypotensive activities of Amifostine.
ArdeparinArdeparin may increase the hyperkalemic activities of Aliskiren.
AtorvastatinThe serum concentration of Aliskiren can be increased when it is combined with Atorvastatin.
Azilsartan medoxomilAliskiren may increase the hyperkalemic activities of Azilsartan medoxomil.
BenazeprilAliskiren may increase the hyperkalemic activities of Benazepril.
BrimonidineBrimonidine may increase the antihypertensive activities of Aliskiren.
ButabarbitalButabarbital may increase the hypotensive activities of Aliskiren.
ButethalButethal may increase the hypotensive activities of Aliskiren.
CanagliflozinCanagliflozin may increase the hyperkalemic activities of Aliskiren.
CandesartanAliskiren may increase the hyperkalemic activities of Candesartan.
CaptoprilAliskiren may increase the hyperkalemic activities of Captopril.
CelecoxibCelecoxib may decrease the antihypertensive activities of Aliskiren.
CilazaprilAliskiren may increase the hyperkalemic activities of Cilazapril.
CyclosporineThe serum concentration of Aliskiren can be increased when it is combined with Cyclosporine.
DalteparinDalteparin may increase the hyperkalemic activities of Aliskiren.
DiazoxideDiazoxide may increase the hypotensive activities of Aliskiren.
DiclofenacDiclofenac may decrease the antihypertensive activities of Aliskiren.
DiflunisalDiflunisal may decrease the antihypertensive activities of Aliskiren.
DrospirenoneDrospirenone may increase the hyperkalemic activities of Aliskiren.
DuloxetineAliskiren may increase the orthostatic hypotensive activities of Duloxetine.
EnalaprilAliskiren may increase the hyperkalemic activities of Enalapril.
EnalaprilatAliskiren may increase the hyperkalemic activities of Enalaprilat.
EnoxaparinEnoxaparin may increase the hyperkalemic activities of Aliskiren.
EprosartanAliskiren may increase the hyperkalemic activities of Eprosartan.
EtodolacEtodolac may decrease the antihypertensive activities of Aliskiren.
FenoprofenFenoprofen may decrease the antihypertensive activities of Aliskiren.
FloctafenineFloctafenine may decrease the antihypertensive activities of Aliskiren.
FlurbiprofenFlurbiprofen may decrease the antihypertensive activities of Aliskiren.
FosinoprilAliskiren may increase the hyperkalemic activities of Fosinopril.
FurosemideThe serum concentration of Furosemide can be decreased when it is combined with Aliskiren.
HeparinHeparin may increase the hyperkalemic activities of Aliskiren.
HeptabarbitalHeptabarbital may increase the hypotensive activities of Aliskiren.
HexobarbitalHexobarbital may increase the hypotensive activities of Aliskiren.
IbuprofenIbuprofen may decrease the antihypertensive activities of Aliskiren.
IndomethacinIndomethacin may decrease the antihypertensive activities of Aliskiren.
InfliximabInfliximab may decrease the antihypertensive activities of Aliskiren.
IrbesartanAliskiren may increase the hyperkalemic activities of Irbesartan.
ItraconazoleThe serum concentration of Aliskiren can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Aliskiren can be increased when it is combined with Ketoconazole.
KetoprofenKetoprofen may decrease the antihypertensive activities of Aliskiren.
KetorolacKetorolac may decrease the antihypertensive activities of Aliskiren.
LevodopaAliskiren may increase the orthostatic hypotensive activities of Levodopa.
LisinoprilAliskiren may increase the hyperkalemic activities of Lisinopril.
LosartanAliskiren may increase the hyperkalemic activities of Losartan.
LumacaftorThe serum concentration of Aliskiren can be decreased when it is combined with Lumacaftor.
Mefenamic acidMefenamic acid may decrease the antihypertensive activities of Aliskiren.
MeloxicamMeloxicam may decrease the antihypertensive activities of Aliskiren.
MethohexitalMethohexital may increase the hypotensive activities of Aliskiren.
MethylphenidateMethylphenidate may decrease the antihypertensive activities of Aliskiren.
MoexiprilAliskiren may increase the hyperkalemic activities of Moexipril.
MolsidomineMolsidomine may increase the hypotensive activities of Aliskiren.
MoxonidineMoxonidine may increase the hypotensive activities of Aliskiren.
NabumetoneNabumetone may decrease the antihypertensive activities of Aliskiren.
NadroparinNadroparin may increase the hyperkalemic activities of Aliskiren.
NaproxenNaproxen may decrease the antihypertensive activities of Aliskiren.
NicorandilNicorandil may increase the hyperkalemic activities of Aliskiren.
ObinutuzumabAliskiren may increase the hypotensive activities of Obinutuzumab.
OlmesartanAliskiren may increase the hyperkalemic activities of Olmesartan.
OxaprozinOxaprozin may decrease the antihypertensive activities of Aliskiren.
PentobarbitalPentobarbital may increase the hypotensive activities of Aliskiren.
PentoxifyllinePentoxifylline may increase the hypotensive activities of Aliskiren.
PerindoprilAliskiren may increase the hyperkalemic activities of Perindopril.
PhenelzinePhenelzine may increase the hypotensive activities of Aliskiren.
PiroxicamPiroxicam may decrease the antihypertensive activities of Aliskiren.
Potassium ChloridePotassium Chloride may increase the hyperkalemic activities of Aliskiren.
Potassium CitratePotassium Citrate may increase the hyperkalemic activities of Aliskiren.
Potassium IodidePotassium Iodide may increase the hyperkalemic activities of Aliskiren.
PrimidonePrimidone may increase the hypotensive activities of Aliskiren.
QuinaprilAliskiren may increase the hyperkalemic activities of Quinapril.
QuinineQuinine may increase the hypotensive activities of Aliskiren.
RamiprilAliskiren may increase the hyperkalemic activities of Ramipril.
RanolazineThe serum concentration of Aliskiren can be increased when it is combined with Ranolazine.
RisperidoneAliskiren may increase the hypotensive activities of Risperidone.
RituximabAliskiren may increase the hypotensive activities of Rituximab.
SaquinavirThe serum concentration of Aliskiren can be increased when it is combined with Saquinavir.
SecobarbitalSecobarbital may increase the hypotensive activities of Aliskiren.
SulindacSulindac may decrease the antihypertensive activities of Aliskiren.
TadalafilTadalafil may increase the antihypertensive activities of Aliskiren.
TelmisartanAliskiren may increase the hyperkalemic activities of Telmisartan.
TesmilifeneThe serum concentration of Aliskiren can be decreased when it is combined with Tesmilifene.
Tiaprofenic acidTiaprofenic acid may decrease the antihypertensive activities of Aliskiren.
TinzaparinTinzaparin may increase the hyperkalemic activities of Aliskiren.
TolmetinTolmetin may decrease the antihypertensive activities of Aliskiren.
TrandolaprilAliskiren may increase the hyperkalemic activities of Trandolapril.
TranylcypromineTranylcypromine may increase the hypotensive activities of Aliskiren.
TreprostinilTreprostinil may increase the hypotensive activities of Aliskiren.
ValsartanAliskiren may increase the hyperkalemic activities of Valsartan.
VardenafilVardenafil may increase the antihypertensive activities of Aliskiren.
VerapamilThe serum concentration of Aliskiren can be increased when it is combined with Verapamil.
YohimbineYohimbine may decrease the antihypertensive activities of Aliskiren.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Receptor binding
Specific Function:
Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
Gene Name:
REN
Uniprot ID:
P00797
Molecular Weight:
45057.125 Da
References
  1. Nussberger J, Wuerzner G, Jensen C, Brunner HR: Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002 Jan;39(1):E1-8. [PubMed:11799102 ]
  2. Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, Ruger H, Goschke R, Stutz S, Fuhrer W, Schilling W, Rigollier P, Yamaguchi Y, Cumin F, Baum HP, Schnell CR, Herold P, Mah R, Jensen C, O'Brien E, Stanton A, Bedigian MP: Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun. 2003 Sep 5;308(4):698-705. [PubMed:12927775 ]
  3. Menard J, Guyene TT, Peyrard S, Azizi M: Conformational changes in prorenin during renin inhibition in vitro and in vivo. J Hypertens. 2006 Mar;24(3):529-34. [PubMed:16467656 ]
  4. Azizi M, Webb R, Nussberger J, Hollenberg NK: Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens. 2006 Feb;24(2):243-56. [PubMed:16508564 ]
  5. Gradman AH, Vivas Y: New drugs for hypertension: what do they offer? Curr Hypertens Rep. 2006 Oct;8(5):425-32. [PubMed:16965731 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP: Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515-31. [PubMed:18611061 ]
Comments
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Drug created on October 13, 2014 16:29 / Updated on July 23, 2016 01:54