General
Preferred name
niraparib
Synonyms
MK-4827 ()
Niraparib hydrochloride ()
MK-4827 (tosylate) ()
Niraparib (MK-4827) tosylate ()
MK 4827 tosylate ()
NIRAPARIB TOSYLATE ()
MK-4827 tosylate ()
MK-4827 (tosylate)Niraparib (MK-4827) tosylate ()
MK 4827 ()
MK4827 ()
MK-4827 (PARP-1) ()
MK-4827, HCl salt ()
CT-MK4827 ()
2H-Indazole-7-carboxamide, 2-[4-(3S)-3-piperidinylphenyl] ()
2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ()
Niraparib (tosylate hydrate) ()
Niraparib (hydrochloride) ()
Niraparib (tosylate) ()
MK-4827 (tosylate hydrate) ()
MK-4827 (hydrochloride) ()
Niraparib (MK-4827) ()
Niraparib tosylate, MK 4827 tosylate, ZEJULA ()
ZL-2306 ()
Zejula ()
JNJ-64091742 ()
MK-4827-TOSYLATE ()
Niraparib tosylate anhydrous ()
Niraparib tosylate monohydrate ()
P&D ID
PD012925
CAS
1038915-73-9
1038915-60-4
1613220-15-7
1038915-64-8
Tags
available
probe
drug
Approved by
PMDA
EMA
FDA
First approval
2017
Drug Status
investigational
approved
Drug indication
Ovarian cancer
Ewing sarcoma
Fallopian tube cancer
Peritoneal cancer
Breast cancer
Max Phase
Phase 4
Probe info
Probe selectivity
family-selective
Probe type
P&D approved
calculated probe
experimental probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Probe control not defined
Orthogonal probes
9
No orthogonal probes found
Similar probes
1
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA
Catalytic inhibitor;PARP-DNA complex trapping
DESCRIPTION
Niraparib is a novel orally available poly(ADP-ribose) polymerase (PARP) inhibitor .
(GtoPdb)
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.
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.
COMMENT
Though this looks like a good tool compound for PARPs, due to the issues with other PARP inhibitors, it would be a good idea to use this probe side-by-side with a structurally distinct inhibitor to cross-validate results. Aug 22 2016 - 12:18pm; Niraparib is a PARP 1/2 inhibitor. This agent is an excellent tool to study PARP inhibition in both the cellular and in vivo setting. However, an important study about the mechanism of these probes appeared in 2012 (Murai et al., Cancer Res. 2012, 72, 5588-5599). In this study, the authors examined the ability of niraparib, olaparib and veliparib to trap PARP1/2 enzymes at the site of DNA damage as opposed to examining merely their activity as inhibitors of the catalytic function of the enzyme. The authors found that the cellular toxicity tracked with the trapping potential (which was different for each drug) rather than each drugs catalytic efficiency (which was similar for each drug). The ranking of each drug for trapping efficiency was found to be niraparib > olaparib >> veliparib. Investigators should thoroughly evaluate their needs when choosing the appropriate PARP inhibitor based upon this altered mechanistic insight. Sep 8 2016 - 11:35am; The compound is reported to be a potent and selective PARP1/2 inhibitor. I have no significant concerns about recommending this compound for use as a chemical probe. In an ideal world, an inactive, closely related analogue would be available for use as a "negative control" but I have been unable to identify one from the literature. To mitigate against the risk of effects caused by unknown, off-target activity (broad profiling has not, to my knowledge, been published), carrying out studies using this alongside a structurally distinct PARP inhibitor is recommended, where possible. Jan 3 2017 - 11:56am; I completely agree with the current reviews recommending researchers to understand their needs and combine their selection with an orthogonal (positive) control or another PARP1/2 inhibitor that acts via a different mechanism or has a different chemotype. If possible, I suggest including a negative control for cell-based assays. Niraparib is in clinical trials. Does this mean that it is a chemical probe? In this case, it does not satisfy the criteria outlined by Workman and Collins (DOI 10.1016/j.chembiol.2010.05.013). Based on Thorsell et al. (DOI: : 10.1021/acs.jmedchem.6b00990), niraparib inhibits PARP12. Within the family of PARPs, PARP1 and PARP2 are sub-branches on the same main branch while PARP12 is much further removed. To my knowledge, off-target screening data characterizing its activity against kinases, GPCRs, and other likely targets has also not been published. There is also potential off-target inhibition on deoxycitidine kinase (http://dx.doi.org/10.1016/j.chembiol.2016.10.011). May 17 2017 - 12:49pm
MOA
Catalytic inhibitor, PARP-DNA complex trapping
(Chemical Probes.org)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
3
Organisms
0
Compound Sets
24
AdooQ Bioactive Compound Library
Axon Medchem Screening Library
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Chemical Probes.org
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP Approved Drugs
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
High-quality chemical probes
LSP-MoA library (Laboratory of Systems Pharmacology)
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
ReFrame library
Selleckchem Bioactive Compound Library
Tool Compound Set
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
65
Molecular Weight
320.16
Hydrogen Bond Acceptors
4
Hydrogen Bond Donors
2
Rotatable Bonds
3
Ring Count
4
Aromatic Ring Count
3
cLogP
2.59
TPSA
72.94
Fraction CSP3
0.26
Chiral centers
1.0
Largest ring
6.0
QED
0.78
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
Poly [ADP-ribose] polymerase-1
Poly [ADP-ribose] polymerase 2
PARP1
PARP2
TANK-1
PARP3
V-PARP
Apoptosis related,PARP
PARP1, PARP2
Pathway
Chromatin/Epigenetic
DNA Damage/DNA Repair
Apoptosis
Cell Cycle/DNA Damage
Epigenetics
Indication
primary peritoneal cancer (PPC)
MOA
PARP inhibitor
Orthogonal probe
Olaparib
Target subclass
PARP
PARP, PARP
Target class
Other post-translational modification
Other post-translational modification, Other post-translational modification
Therapeutic Class
Antihypertensive Agents
Source data
