Identification

Name
Niraparib
Accession Number
DB11793
Type
Small Molecule
Groups
Approved, Investigational
Description

Niraparib is an orally active PARP inhibitor developed by Tesaro to treat ovarian cancer. FDA approval on March 2017.

Structure
Thumb
Synonyms
Not Available
External IDs
MK 4827 / MK-4827 / MK-4827 FREE BASE / MK4827
Product Ingredients
IngredientUNIICASInChI Key
Niraparib hydrochlorideL4JFC1PHCI1038915-64-8YXYDNYFWAFBCAN-PFEQFJNWSA-N
Niraparib tosylate75KE12AY9U1038915-73-9LCPFHXWLJMNKNC-PFEQFJNWSA-N
Niraparib tosylate monohydrate195Q483UZD1613220-15-7ACNPUCQQZDAPJH-FMOMHUKBSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZejulaCapsule100 mg/1OralTesaro, Inc.2017-03-27Not applicableUs
Categories
UNII
HMC2H89N35
CAS number
1038915-60-4
Weight
Average: 320.396
Monoisotopic: 320.16371128
Chemical Formula
C19H20N4O
InChI Key
PCHKPVIQAHNQLW-CQSZACIVSA-N
InChI
InChI=1S/C19H20N4O/c20-19(24)17-5-1-3-15-12-23(22-18(15)17)16-8-6-13(7-9-16)14-4-2-10-21-11-14/h1,3,5-9,12,14,21H,2,4,10-11H2,(H2,20,24)/t14-/m1/s1
IUPAC Name
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
SMILES
NC(=O)C1=CC=CC2=CN(N=C12)C1=CC=C(C=C1)[C@@H]1CCCNC1

Pharmacology

Indication

Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy

Associated Conditions
Pharmacodynamics

Cardiovascular Effects: Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT). In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively.
Cardiac Electrophysiology The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo-controlled trial in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily.

Mechanism of action

Niraparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2.

TargetActionsOrganism
APoly [ADP-ribose] polymerase 1
antagonist
Human
APoly [ADP-ribose] polymerase 2
antagonist
Human
Absorption

The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours. Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib.
Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL. The systemic exposures (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg.

Volume of distribution

The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L.

Protein binding

Niraparib is 83.0% bound to human plasma proteins.

Metabolism

Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation.

Route of elimination

Following administration of a single oral 300 mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces.

Half life

Following multiple daily doses of 300 mg niraparib, the mean half-life (t1/2) is 36 hours.

Clearance

the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Chen A: PARP inhibitors: its role in treatment of cancer. Chin J Cancer. 2011 Jul;30(7):463-71. doi: 10.5732/cjc.011.10111. [PubMed:21718592]
  2. FDA approval [Link]
  3. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors [Link]
  4. FDA label [Link]
External Links
PubChem Compound
24958200
PubChem Substance
347828142
ChemSpider
24531930
BindingDB
50316226
ChEMBL
CHEMBL1094636
PharmGKB
PA166131610
HET
3JD
Wikipedia
Niraparib
PDB Entries
4r6e

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherAdvanced Solid Tumors1
1Active Not RecruitingTreatmentCancer of the Ovary1
1Active Not RecruitingTreatmentEwing's Sarcoma (ES)1
1CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / T-cell-prolymphocytic Leukemia / Tumors, Solid1
1CompletedTreatmentGlioblastoma Multiforme (GBM) / Melanoma / Recurrence of Solid Tumor1
1CompletedTreatmentMalignancies1
1Not Yet RecruitingTreatmentCancer of the Ovary1
1Not Yet RecruitingTreatmentDeleterious BRCA1 Gene Mutation / Deleterious BRCA2 Gene Mutation / Endometrial Adenocarcinomas / High Grade Ovarian Serous Adenocarcinoma / Primary Peritoneal High Grade Serous Adenocarcinoma / Recurrent Endometrial Carcinoma / Recurrent Fallopian Tube Carcinoma / Recurrent Ovarian Carcinoma / Recurrent Primary Peritoneal Carcinoma1
1RecruitingTreatmentBRCA1 Gene Mutation / Brca2 Gene Mutation / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast1
1RecruitingTreatmentCancer of the Ovary / Cancer, Breast1
1RecruitingTreatmentCancer, Advanced / Metastatic Cancers / Tumors, Solid1
1RecruitingTreatmentHepatic Impairment / Tumors, Solid1
1RecruitingTreatmentHomologous Recombination Deficiency / Solid Tumor, Adult1
1RecruitingTreatmentHormone-Refractory Prostate Cancer / Prostate Carcinoma Metastatic to the Bone / Stage IV Prostate Adenocarcinoma1
1RecruitingTreatmentProstatic Neoplasms1
1RecruitingTreatmentTumors, Solid1
1TerminatedTreatmentCancer: Solid Tumors1
1TerminatedTreatmentMetastatic Hormone Refractory Prostate Cancer1
1TerminatedTreatmentNeoplasms / Tumors, Solid1
1, 2Active Not RecruitingTreatmentAdvanced Breast Cancer / Cancer of the Ovary / Cancer, Breast / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm / Metastatic Breast Cancer (MBC) / Stage IV Breast Cancer / Triple Negative Breast Cancer (TNBC)1
1, 2Active Not RecruitingTreatmentCancer of the Ovary1
1, 2Not Yet RecruitingTreatmentHER2 Positive Breast Carcinoma / Metastatic Breast Cancer (MBC)1
1, 2Not Yet RecruitingTreatmentMetastatic Carcinoma of the Cervix1
1, 2RecruitingTreatmentAdenocarcinoma of the Pancreas1
1, 2RecruitingTreatmentProstatic Neoplasms, Castration-Resistant1
2Active Not RecruitingTreatmentCancer of the Ovary1
2Not Yet RecruitingTreatmentMalignant Neoplasm of Pancreas1
2RecruitingTreatmentCancer of the Ovary1
2RecruitingTreatmentCancer of the Ovary / Fallopian Tube Cancer / Primary Peritoneal Carcinoma1
2RecruitingTreatmentCancer, Breast1
2RecruitingTreatmentCholangiocarcinomas / Mesothelioma / Renal Cell Adenocarcinoma / Uveal Melanoma1
2RecruitingTreatmentEndometrial Cancers1
2RecruitingTreatmentMalignant Neoplasm of Pancreas1
2RecruitingTreatmentNeoplasms, Lung1
2RecruitingTreatmentProstatic Neoplasms1
2WithdrawnTreatmentMalignant Lymphomas / Mantle-Cell1
2, 3Not Yet RecruitingTreatmentEndometrial Carcinosarcoma / Ovarian Carcinosarcoma1
3Active Not RecruitingTreatmentBRCA1 Gene Mutation / Brca2 Gene Mutation / Carcinoma of Breast / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast1
3Active Not RecruitingTreatmentCancer of the Ovary1
3CompletedTreatmentPlatinum Sensitive Ovarian Cancer1
3Not Yet RecruitingTreatmentRecurrent Ovarian Carcinoma1
3RecruitingTreatmentCancer of the Ovary1
Not AvailableAvailableNot AvailableRecurrent Ovarian Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral100 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8071623No2010-03-222030-03-22Us
US8436185No2009-04-242029-04-24Us

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0149 mg/mLALOGPS
logP2.45ALOGPS
logP2.47ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)14.03ChemAxon
pKa (Strongest Basic)10.1ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area72.94 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity94.92 m3·mol-1ChemAxon
Polarizability36.41 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Phenylpyrazoles / Indazoles / Aralkylamines / Benzene and substituted derivatives / Heteroaromatic compounds / Primary carboxylic acid amides / Amino acids and derivatives / Dialkylamines / Azacyclic compounds / Organooxygen compounds
show 2 more
Substituents
Phenylpiperidine / Phenylpyrazole / Benzopyrazole / Indazole / Aralkylamine / Benzenoid / Monocyclic benzene moiety / Heteroaromatic compound / Pyrazole / Azole
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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 ...
Gene Name
PARP1
Uniprot ID
P09874
Uniprot Name
Poly [ADP-ribose] polymerase 1
Molecular Weight
113082.945 Da
References
  1. PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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 ...
Gene Name
PARP2
Uniprot ID
Q9UGN5
Uniprot Name
Poly [ADP-ribose] polymerase 2
Molecular Weight
66205.31 Da
References
  1. PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Carboxylic ester hydrolase activity
Specific Function
Not Available
Gene Name
CES1A1a
Uniprot ID
Q6LAP9
Uniprot Name
Carboxylesterase
Molecular Weight
1908.25 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Receptor binding
Specific Function
Plays an important role in the degradation of dermatan and keratan sulfates.
Gene Name
GUSB
Uniprot ID
P08236
Uniprot Name
Beta-glucuronidase
Molecular Weight
74731.46 Da

Drug created on October 20, 2016 14:48 / Updated on November 14, 2018 13:02