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Identification
NameOlaparib
Accession NumberDB09074
TypeSmall Molecule
GroupsApproved
Description

Lynparza is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

Structure
Thumb
Synonyms
4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one
External Identifiers
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU59436
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Lynparzacapsule50 mg/1oralAstra Zeneca Pharmaceuticals Lp2014-12-24Not applicableUs
Lynparzacapsule50 mgoralAstrazeneca Canada Inc2016-05-16Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIWOH1JD9AR8
CAS number763113-22-0
WeightAverage:
Monoisotopic:
Chemical FormulaNot Available
InChI KeyNot Available
InChI
IUPAC Name
4-{[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorophenyl]methyl}phthalazin-1-ol
SMILES
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phthalazinones. These are compounds containing a phthalazine bearing a ketone group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassPhthalazines
Direct ParentPhthalazinones
Alternative Parents
Substituents
  • Phthalazinone
  • Halobenzoic acid or derivatives
  • 2-halobenzoic acid or derivatives
  • Benzoic acid or derivatives
  • Benzamide
  • Benzoyl
  • Pyridazinone
  • Halobenzene
  • Fluorobenzene
  • Benzenoid
  • Pyridazine
  • Piperazine
  • 1,4-diazinane
  • Cyclopropanecarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Vinylogous halide
  • Tertiary carboxylic acid amide
  • Tertiary amine
  • Lactam
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationOlaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
PharmacodynamicsNot Available
Mechanism of actionOlaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.
Related Articles
AbsorptionPeak plasma concentrations achieved typically between 1 to 3 hours following oral administration of olaparib in capsule formulation.
Volume of distribution

167 +/-196 L following a single dose of 400mg olaparib.

Protein bindingApproximately 82%.
Metabolism

Primarily CYP3A4 in vitro.

Route of elimination44% via the urine and 42% via the feces.
Half life11.9 hours, standard deviation 4.8 hours.
Clearance

8.6 +/- 7.1L/h.

ToxicityThe most commonly reported side effects reported during clinical trials included cough, constipation, dysguesia, peripheral deem, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in 2% of patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers. The majority of cases were fatal and the duration of therapy with olaparib in patients who developed secondary cancers varied from <6 months to >2 years. Complete blood count should be tested at baseline and monthly following therapy initiation to monitor for MDS/AML. Pneumonitis, including fatal cases, occurred in <1% of patients treated with olaparib. Patients should be monitored for new or worsening respiratory symptoms such as dyspnea, fever, cough, or wheezing. Olaparib was found to be teratogenic and causes embryo-fetal toxicity in rats. It should therefore be avoided during pregnancy and its use should be a combined with an effective contraception during treatment.
Affected organismsNot Available
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
Capsuleoral50 mg/1
Capsuleoral50 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7151102 No2002-04-292022-04-29Us
US7449464 No2004-10-112024-10-11Us
US7981889 No2004-10-112024-10-11Us
US8143241 No2007-08-122027-08-12Us
US8247416 No2008-09-242028-09-24Us
US8859562 No2011-08-042031-08-04Us
US8912187 No2004-03-122024-03-12Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.119 mg/mLALOGPS
logP2.68ALOGPS
logP2.32ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)8.75ChemAxon
pKa (Strongest Basic)2.21ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area86.63 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity118.63 m3·mol-1ChemAxon
Polarizability44.03 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference
  1. Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM Jr, Matthews IT, Moore S, O’Connor MJ, Smith GC, Martin NM: 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin- 1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. Pubmed
General References
  1. Frampton JE: Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. BioDrugs. 2015 Apr;29(2):143-50. doi: 10.1007/s40259-015-0125-6. [PubMed:25899311 ]
  2. Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM Jr, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM: 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin- 1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. [PubMed:18800822 ]
  3. Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O'Connor M, Clarke AR: Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009 May 1;69(9):3850-5. doi: 10.1158/0008-5472.CAN-08-2388. Epub 2009 Apr 21. [PubMed:19383921 ]
  4. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J: High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29. [PubMed:18971340 ]
External Links
ATC CodesL01XX46
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (297 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of Olaparib can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Olaparib can be increased when it is combined with Atazanavir.
BexaroteneThe serum concentration of Olaparib can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Olaparib can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Olaparib can be decreased when it is combined with Bosentan.
CarbamazepineThe serum concentration of Olaparib can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Olaparib can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Olaparib can be increased when it is combined with Clarithromycin.
ClozapineThe risk or severity of adverse effects can be increased when Olaparib is combined with Clozapine.
CobicistatThe serum concentration of Olaparib can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Olaparib can be increased when it is combined with Conivaptan.
CrizotinibThe serum concentration of Olaparib can be increased when it is combined with Crizotinib.
DabrafenibThe serum concentration of Olaparib can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Olaparib can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Olaparib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Olaparib can be decreased when it is combined with Deferasirox.
DelavirdineThe serum concentration of Olaparib can be increased when it is combined with Delavirdine.
DexamethasoneThe serum concentration of Olaparib can be decreased when it is combined with Dexamethasone.
DiltiazemThe serum concentration of Olaparib can be increased when it is combined with Diltiazem.
DronedaroneThe serum concentration of Olaparib can be increased when it is combined with Dronedarone.
EfavirenzThe serum concentration of Olaparib can be decreased when it is combined with Efavirenz.
EnzalutamideThe serum concentration of Olaparib can be decreased when it is combined with Enzalutamide.
ErythromycinThe serum concentration of Olaparib can be increased when it is combined with Erythromycin.
Eslicarbazepine acetateThe serum concentration of Olaparib can be decreased when it is combined with Eslicarbazepine acetate.
EtravirineThe serum concentration of Olaparib can be decreased when it is combined with Etravirine.
FluconazoleThe serum concentration of Olaparib can be increased when it is combined with Fluconazole.
FosamprenavirThe serum concentration of Olaparib can be increased when it is combined with Fosamprenavir.
FosaprepitantThe serum concentration of Olaparib can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of Olaparib can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Olaparib can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Olaparib can be increased when it is combined with Idelalisib.
ImatinibThe serum concentration of Olaparib can be increased when it is combined with Imatinib.
IndinavirThe serum concentration of Olaparib can be increased when it is combined with Indinavir.
IsavuconazoniumThe serum concentration of Olaparib can be increased when it is combined with Isavuconazonium.
ItraconazoleThe serum concentration of Olaparib can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Olaparib can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Olaparib can be increased when it is combined with Ketoconazole.
LuliconazoleThe serum concentration of Olaparib can be increased when it is combined with Luliconazole.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Olaparib.
MifepristoneThe serum concentration of Olaparib can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Olaparib can be decreased when it is combined with Mitotane.
ModafinilThe serum concentration of Olaparib can be decreased when it is combined with Modafinil.
NafcillinThe serum concentration of Olaparib can be decreased when it is combined with Nafcillin.
NefazodoneThe serum concentration of Olaparib can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Olaparib can be increased when it is combined with Nelfinavir.
NilotinibThe serum concentration of Olaparib can be increased when it is combined with Nilotinib.
PalbociclibThe serum concentration of Olaparib can be increased when it is combined with Palbociclib.
PhenobarbitalThe serum concentration of Olaparib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Olaparib can be decreased when it is combined with Phenytoin.
PosaconazoleThe serum concentration of Olaparib can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of Olaparib can be decreased when it is combined with Primidone.
RifabutinThe serum concentration of Olaparib can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Olaparib can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Olaparib can be decreased when it is combined with Rifapentine.
RitonavirThe serum concentration of Olaparib can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Olaparib can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Olaparib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Olaparib can be increased when it is combined with Simeprevir.
StiripentolThe serum concentration of Olaparib can be increased when it is combined with Stiripentol.
TelaprevirThe serum concentration of Olaparib can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Olaparib can be increased when it is combined with Telithromycin.
TocilizumabThe serum concentration of Olaparib can be decreased when it is combined with Tocilizumab.
VerapamilThe serum concentration of Olaparib can be increased when it is combined with Verapamil.
VoriconazoleThe serum concentration of Olaparib can be increased when it is combined with Voriconazole.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR...
Gene Name:
PARP1
Uniprot ID:
P09874
Molecular Weight:
113082.945 Da
References
  1. Verhagen CV, de Haan R, Hageman F, Oostendorp TP, Carli AL, O'Connor MJ, Jonkers J, Verheij M, van den Brekel MW, Vens C: Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells. Radiother Oncol. 2015 Sep;116(3):358-65. doi: 10.1016/j.radonc.2015.03.028. Epub 2015 May 13. [PubMed:25981132 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
Inhibitor
General Function:
Nad+ adp-ribosyltransferase activity
Specific Function:
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks.
Gene Name:
PARP2
Uniprot ID:
Q9UGN5
Molecular Weight:
66205.31 Da
References
  1. Verhagen CV, de Haan R, Hageman F, Oostendorp TP, Carli AL, O'Connor MJ, Jonkers J, Verheij M, van den Brekel MW, Vens C: Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells. Radiother Oncol. 2015 Sep;116(3):358-65. doi: 10.1016/j.radonc.2015.03.028. Epub 2015 May 13. [PubMed:25981132 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
Inhibitor
General Function:
Nad+ adp-ribosyltransferase activity
Specific Function:
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. May link the DNA damage surveillance network to the ...
Gene Name:
PARP3
Uniprot ID:
Q9Y6F1
Molecular Weight:
60069.7 Da
References
  1. Verhagen CV, de Haan R, Hageman F, Oostendorp TP, Carli AL, O'Connor MJ, Jonkers J, Verheij M, van den Brekel MW, Vens C: Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells. Radiother Oncol. 2015 Sep;116(3):358-65. doi: 10.1016/j.radonc.2015.03.028. Epub 2015 May 13. [PubMed:25981132 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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. Verhagen CV, de Haan R, Hageman F, Oostendorp TP, Carli AL, O'Connor MJ, Jonkers J, Verheij M, van den Brekel MW, Vens C: Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells. Radiother Oncol. 2015 Sep;116(3):358-65. doi: 10.1016/j.radonc.2015.03.028. Epub 2015 May 13. [PubMed:25981132 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Steroid 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
References
  1. Verhagen CV, de Haan R, Hageman F, Oostendorp TP, Carli AL, O'Connor MJ, Jonkers J, Verheij M, van den Brekel MW, Vens C: Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells. Radiother Oncol. 2015 Sep;116(3):358-65. doi: 10.1016/j.radonc.2015.03.028. Epub 2015 May 13. [PubMed:25981132 ]
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Drug created on May 14, 2015 14:38 / Updated on June 29, 2016 01:52