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Identification
NamePrasugrel
Accession NumberDB06209
Typesmall molecule
Groupsapproved
Description

Prasugrel, a thienopyridine derivative, is a platelet activation and aggregation inhibitor structurally and pharmacologically related to clopidogrel and ticlopidine. Similar to clopidogrel, prasugrel is a prodrug that requires enzymatic transformation in the liver to its active metabolite, R-138727. R-138727 irreversibly binds to P2Y12 type ADP receptors on platelets thus preventing activation of the GPIIb/IIIa receptor complex. As a result, inhibition of ADP-mediated platelet activation and aggregation occurs. Prasugrel was developed by Daiichi Sankyo Co. and is currently marketed in the United States and Canada in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI). FDA approved in 2009.

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Prasugrel Hydrochloride
Thumb
  • InChI Key: JALHGCPDPSNJNY-UHFFFAOYNA-N
  • Monoisotopic Mass: 409.091470145
  • Average Mass: 409.902
DBSALT000145
Brand names
NameCompany
EffientDaiichi Sankyo Co.
EfientDaiichi Sankyo Co.
PrasitaDaiichi Sankyo Co.
Brand mixturesNot Available
Categories
CAS number150322-43-3
WeightAverage: 373.441
Monoisotopic: 373.114792406
Chemical FormulaC20H20FNO3S
InChI KeyDTGLZDAWLRGWQN-UHFFFAOYSA-N
InChI
InChI=1S/C20H20FNO3S/c1-12(23)25-18-10-14-11-22(9-8-17(14)26-18)19(20(24)13-6-7-13)15-4-2-3-5-16(15)21/h2-5,10,13,19H,6-9,11H2,1H3
IUPAC Name
5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4H,5H,6H,7H-thieno[3,2-c]pyridin-2-yl acetate
SMILES
CC(=O)OC1=CC2=C(CCN(C2)C(C(=O)C2CC2)C2=CC=CC=C2F)S1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenylpropylamines
Direct parentPhenylpropylamines
Alternative parentsThienopyridines; Alkyl Aryl Ethers; Fluorobenzenes; Pyridines and Derivatives; Cyclopropanecarboxylic Acids and Derivatives; Aryl Fluorides; Thiophenes; Ketones; Tertiary Amines; Carboxylic Acid Esters; Polyamines; Enolates; Organofluorides
Substituentsalkyl aryl ether; fluorobenzene; cyclopropanecarboxylic acid or derivative; pyridine; aryl halide; aryl fluoride; thiophene; tertiary amine; carboxylic acid ester; ketone; enolate; polyamine; ether; carboxylic acid derivative; organofluoride; carbonyl group; organonitrogen compound; amine; organohalogen
Classification descriptionThis compound belongs to the phenylpropylamines. These are compounds containing a phenylpropylamine moiety, which consists of a phenyl group substituted at the third carbon by an propan-1-amine.
Pharmacology
IndicationIndicated in combination with acetylsalicylic acid (ASA) to prevent atherothrombotic events in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI). May be used in patients with unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI) who are to be managed with PCI. Prasugrel is not recommended in patients 75 years of age or greater, those that weigh<60kg, and patients with a history of stroke or transient ischemic attack due to increased risk of fatal and intracranial bleeding.
PharmacodynamicsPrasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors. Compared to clopidogrel, prasugrel inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI. The increased potency of prasugrel appears to be due to more efficient conversion to its active metabolite. However, it carries a higher risk of bleed compared to clopidogrel, which may be a result of its higher potency. Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.
Mechanism of actionPrasugrel is an thienopyridine and a prodrug which inhibits ADP receptors by irreversibly acting on the P2Y12 receptor on platelets. The active metabolite of prasugrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Prasugrel is proposed to have a similar mechanism of action to clopidogrel.
Absorption79% or greater of the dose is absorbed after oral administration. Absorption and metabolism occur rapidly and peak plasma concentrations (Cmax) are reached approximately 30 minutes following oral administration. Administration with a high fat, high calorie meal did not affect the AUC of the active metabolite in healthy individuals, but the Cmax was decreased by ~49% and the Tmax was increased to 0.5 to 1.5 hours. Prasugrel may be administered with or without food.
Volume of distribution

44-68L

Protein bindingApproximately 98% of the active metabolite was bound to human serum albumin in a 4% buffered solution. The major inactive metabolites are also highly bound to human plasma proteins.
Metabolism

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to thiolactone by human carboxylesterase (hCE) 2. This intermediate is further metabolized to its active metabolite, R-138727, in a single step by cytochrome P450 enzymes in the liver (primarily CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19). The active metabolite is further metabolized by S-methylation or cysteine conjugation to two inactive metabolites. Unlike clopidogrel, transformation of prasugrel to its active metabolite does not appear to be affected by cytochrome P450 polymorphisms.

SubstrateEnzymesProduct
Prasugrel
R-95913Details
R-95913
R-138727Details
Route of eliminationApproximately 68% of the orally administered dose is excreted in urine and 27% in the feces, as inactive metabolites. The active metabolite is not expected to be removed by dialysis.
Half lifeThe active metabolite has an elimination half-life of about 7.4 hours (range 2-15 hours).
Clearance

Apparent clearance = 112 – 166 L/hr

ToxicityLD50 (rat) 1,000 - 2,000 mg/kg; LD50 (rabbit) > 1,000 mg/kg
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 + 1.0
Blood Brain Barrier + 0.9352
Caco-2 permeable + 0.5325
P-glycoprotein substrate Substrate 0.767
P-glycoprotein inhibitor I Inhibitor 0.6555
P-glycoprotein inhibitor II Non-inhibitor 0.7365
Renal organic cation transporter Inhibitor 0.5312
CYP450 2C9 substrate Non-substrate 0.7508
CYP450 2D6 substrate Non-substrate 0.7371
CYP450 3A4 substrate Substrate 0.5402
CYP450 1A2 substrate Non-inhibitor 0.5288
CYP450 2C9 substrate Non-inhibitor 0.5706
CYP450 2D6 substrate Non-inhibitor 0.7051
CYP450 2C19 substrate Inhibitor 0.7083
CYP450 3A4 substrate Non-inhibitor 0.7432
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8719
Ames test Non AMES toxic 0.6616
Carcinogenicity Non-carcinogens 0.9521
Biodegradation Not ready biodegradable 0.9961
Rat acute toxicity 2.4834 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7927
hERG inhibition (predictor II) Non-inhibitor 0.6438
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral5 mg, 10 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States66931152001-07-032021-07-03
United States52887261992-09-082012-09-08
Canada20776952002-08-202012-09-08
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP3.536MSDS
Predicted Properties
PropertyValueSource
water solubility2.37e-03 g/lALOGPS
logP3.67ALOGPS
logP4.31ChemAxon
logS-5.2ALOGPS
pKa (strongest acidic)14.25ChemAxon
pKa (strongest basic)5.48ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count0ChemAxon
polar surface area46.61ChemAxon
rotatable bond count6ChemAxon
refractivity96.81ChemAxon
polarizability37.7ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Teruhiko Inoue, Kazuyoshi Nakamura, Masahiko Hagihara, Hiroyuki Miyata, Yukinori Wada, Naoyuki Yokota, “Process for Producing High-Purity Prasugrel and Acid Addition Salt Thereof.” U.S. Patent US20090203729, issued August 13, 2009.

US20090203729
General Reference
  1. Dovlatova NL, Jakubowski JA, Sugidachi A, Heptinstall S: The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost. 2008 May 15;. Pubmed
  2. Tagarakis GI: Ticagrelor and Prasugrel: Two Novel, Most-Promising Antiplatelet Agents. Recent Pat Cardiovasc Drug Discov. 2010 Sep 27. Pubmed
  3. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed
  4. Jeong YH, Tantry US, Gurbel PA: Importance of potent P2Y receptor blockade in acute myocardial infarction: focus on prasugrel. Expert Opin Pharmacother. 2012 Aug;13(12):1771-96. doi: 10.1517/14656566.2012.704909. Epub 2012 Jul 12. Pubmed
External Links
ResourceLink
KEGG DrugD05597
PubChem Compound6918456
PubChem Substance99443238
ChemSpider5293653
PharmGKBPA154410481
RxListhttp://www.rxlist.com/effient-drug.htm
Drugs.comhttp://www.drugs.com/cdi/prasugrel.html
PDRhealthhttp://www.pdrhealth.com/drugs/effient
WikipediaPrasugrel
ATC CodesB01AC22
AHFS Codes
  • 20:12.18
PDB EntriesNot Available
FDA labelshow(1000 KB)
MSDSshow(134 KB)
Interactions
Drug Interactions
Drug
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
IbuprofenCoadministration with NSAIDS used chronically may increase the risk of bleeding.
KetoconazoleKetoconazole is a potent inhibitor of CYP3A4 which decreases the Cmax of prasugrel due to a reduction of prasugrel bioactivation. However, there was no reduction of inhibition of platelet aggregation.
LansoprazoleLansoprazole is a CYP2C19 substrate which decreases AUC and Cmax of prasugrel. Despite these decreases, there was no significant reduction of inhibition of platelet aggregation.
RitonavirRitonavir is a inhibitor of CYP3A4, thus blocking the bioactivation of prasugrel. As a result, a reduction in prasugrel efficiency may be observed in patients.
WarfarinCoadministration with warfarin may increase the risk of bleeding.
Food Interactions
  • Despite being a CYP3A4 inducer, grapefruit juice does not affect the pharmacokinetics of prasugrel

Targets

1. P2Y purinoceptor 12

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
P2Y purinoceptor 12 Q9H244 Details

References:

  1. Dovlatova NL, Jakubowski JA, Sugidachi A, Heptinstall S: The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost. 2008 Jul;6(7):1153-9. Epub 2008 Jul 1. Pubmed

Enzymes

1. Cocaine esterase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cocaine esterase O00748 Details

References:

  1. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed

5. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

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Drug created on March 19, 2008 10:17 / Updated on September 16, 2013 18:03