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Identification
NameAliskiren
Accession NumberDB01258
Typesmall molecule
Groupsapproved, investigational
Description

Aliskiren is a renin inhibitor. It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of hypertension.

Structure
Thumb
Synonyms
SynonymLanguageCode
RasilezNot AvailableNot Available
SPP 100Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
RasilezNot Available
TekturnaNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number173334-57-1
WeightAverage: 551.7583
Monoisotopic: 551.393436443
Chemical FormulaC30H53N3O6
InChI KeyInChIKey=UXOWGYHJODZGMF-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[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentDelta Amino Acids and Derivatives
Alternative parentsN-acyl Amines; Beta Amino Acids and Derivatives; Anisoles; Alkyl Aryl Ethers; Primary Carboxylic Acid Amides; Secondary Alcohols; Secondary Carboxylic Acid Amides; 1,2-Aminoalcohols; Carboxylic Acids; Polyamines; Enolates; Monoalkylamines
Substituentsbeta amino acid or derivative; phenol ether; anisole; alkyl aryl ether; benzene; primary carboxylic acid amide; secondary alcohol; 1,2-aminoalcohol; carboxamide group; secondary carboxylic acid amide; carboxylic acid; enolate; polyamine; ether; amine; primary aliphatic amine; primary amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the delta amino acids and derivatives. These are compounds containing a carboxylic acid group and an amino group at the C5 carbon atom.
Pharmacology
IndicationFor the treatment of mild to moderate hypertension. It may be used alone or in combination with other antihypertensive agents.
PharmacodynamicsAliskiren is a nonpeptide renin inhibitor marketed under the trade name Tekturna by Novartis.
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 angiotensin-converting enzyme (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 ACE inhibitors 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. PRA reductions in clinical trials ranged from approximately 50%-80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.
AbsorptionRapidly absorbed following oral administration. Absolute bioavailability = 2.6%
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 life24-41 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
Property Value Probability
Human Intestinal Absorption + 0.6987
Blood Brain Barrier - 0.9615
Caco-2 permeable - 0.7064
P-glycoprotein substrate Substrate 0.8743
P-glycoprotein inhibitor I Non-inhibitor 0.8603
P-glycoprotein inhibitor II Non-inhibitor 0.721
Renal organic cation transporter Non-inhibitor 0.899
CYP450 2C9 substrate Non-substrate 0.8285
CYP450 2D6 substrate Non-substrate 0.653
CYP450 3A4 substrate Substrate 0.5845
CYP450 1A2 substrate Non-inhibitor 0.8673
CYP450 2C9 substrate Non-inhibitor 0.8846
CYP450 2D6 substrate Non-inhibitor 0.7678
CYP450 2C19 substrate Non-inhibitor 0.8444
CYP450 3A4 substrate Non-inhibitor 0.6753
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9831
Ames test Non AMES toxic 0.8027
Carcinogenicity Non-carcinogens 0.8964
Biodegradation Not ready biodegradable 0.9579
Rat acute toxicity 2.5190 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9911
hERG inhibition (predictor II) Non-inhibitor 0.6758
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral150 mg
Tablet, film coatedOral300 mg
Prices
Unit descriptionCostUnit
Tekturna 300 mg tablet3.76USDtablet
Tekturna hct 300-12.5 mg tablet3.69USDtablet
Tekturna hct 300-25 mg tablet3.69USDtablet
Tekturna 150 mg tablet2.94USDtablet
Tekturna hct 150-12.5 mg tablet2.92USDtablet
Tekturna hct 150-25 mg tablet2.92USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States55591111998-07-212018-07-21
Canada21470562005-10-252015-04-13
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityHighly soluble in water (as hemifumarate salt)Not Available
logP3.3Not Available
Predicted Properties
PropertyValueSource
water solubility2.10e-03 g/lALOGPS
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 area146.13ChemAxon
rotatable bond count19ChemAxon
refractivity154.32ChemAxon
polarizability64.25ChemAxon
number of rings1ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Nina FINKELSTEIN, Ariel Mittelman, “ALISKIREN MONOFUMARATE AND PROCESSES FOR PREPARATION THEREOF.” U.S. Patent US20100029774, issued February 04, 2010.

US20100029774
General Reference
  1. 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
  2. Staessen JA, Li Y, Richart T: Oral renin inhibitors. Lancet. 2006 Oct 21;368(9545):1449-56. Pubmed
  3. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP: Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515-31. Pubmed
External Links
ResourceLink
KEGG DrugD03208
PubChem Compound5493444
PubChem Substance46507474
ChemSpider4591452
BindingDB17950
ChEBI601027
ChEMBLCHEMBL1639
Therapeutic Targets DatabaseDAP001219
PharmGKBPA143487910
Drugs.comhttp://www.drugs.com/cdi/aliskiren.html
WikipediaAliskiren
ATC CodesC09XA02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
Azilsartan medoxomilAzilsartan medoxomil used in combination with aliskiren may lead to hyperkalemia, hypotension, and nephrotoxicity.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food InteractionsNot Available

1. Renin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Renin P00797 Details

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
  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
  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
  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
  5. Gradman AH, Vivas Y: New drugs for hypertension: what do they offer? Curr Hypertens Rep. 2006 Oct;8(5):425-32. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Comments
Drug created on May 16, 2007 11:25 / Updated on September 16, 2013 17:13