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Identification
Name Aliskiren
Accession Number DB01258
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Rasilez
SPP 100
Salts Not Available
Brand names
Name Company
Rasilez
Tekturna
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
CAS number 173334-57-1
Weight Average: 551.7583
Monoisotopic: 551.393436443
Chemical Formula C30H53N3O6
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbonyl Compounds
  • Phenols and Derivatives
  • Ethers
  • Catechols
  • Anisoles
  • Phenyl Esters
Substructures
  • Carbonyl Compounds
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Carbamates and Derivatives
  • Amino Alcohols
  • Catechols
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Alcohols and Polyols
  • Phenyl Esters
Pharmacology
Indication For the treatment of mild to moderate hypertension. It may be used alone or in combination with other antihypertensive agents.
Pharmacodynamics Aliskiren is a nonpeptide renin inhibitor marketed under the trade name Tekturna by Novartis.
Mechanism of action Renin 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.
Absorption Rapidly absorbed following oral administration. Absolute bioavailability = 2.6%
Volume of distribution Not Available
Protein binding 47-51%
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 elimination About one fourth of the absorbed dose appears in the urine as parent drug.
Half life 24-41 hours
Clearance Not Available
Toxicity The most likely manifestation of overdosage would be hypotension.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 150 mg
Tablet, film coated Oral 300 mg
Prices
Unit description Cost Unit
Tekturna 300 mg tablet 3.76 USD tablet
Tekturna hct 300-12.5 mg tablet 3.69 USD tablet
Tekturna hct 300-25 mg tablet 3.69 USD tablet
Tekturna 150 mg tablet 2.94 USD tablet
Tekturna hct 150-12.5 mg tablet 2.92 USD tablet
Tekturna hct 150-25 mg tablet 2.92 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5559111 1998-07-21 2018-07-21
Canada 2147056 2005-10-25 2015-04-13
Properties
State solid
Experimental Properties
Property Value Source
water solubility Highly soluble in water (as hemifumarate salt) Not Available
logP 3.3 Not Available
Predicted Properties
Property Value Source
water solubility 2.10e-03 g/l ALOGPS
logP 3.87 ALOGPS
logP 3.12 ChemAxon
logS -5.4 ALOGPS
pKa (strongest acidic) 14.56 ChemAxon
pKa (strongest basic) 9.57 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 7 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 146.13 ChemAxon
rotatable bond count 19 ChemAxon
refractivity 154.32 ChemAxon
polarizability 64.25 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D03208 Link_out
PubChem Compound 5493444 Link_out
PubChem Substance 46507474 Link_out
ChemSpider 4591452 Link_out
BindingDB 17950 Link_out
ChEBI 601027 Link_out
ChEMBL 601027 Link_out
Therapeutic Targets Database DAP001219 Link_out
PharmGKB PA143487910 Link_out
Drugs.com http://www.drugs.com/cdi/aliskiren.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Aliskiren Link_out
ATC Codes
  • C09XA02
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
azilsartan medoxomil Azilsartan medoxomil used in combination with aliskiren may lead to hyperkalemia, hypotension, and nephrotoxicity.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions Not Available
Targets

1. Renin

Pharmacological action: yes
Actions: inhibitor

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

Organism class: human
UniProt ID: P00797 Link_out
Gene: REN Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:20