Details of the Drug

General Information of Drug (ID: DMLYGH4)

Drug Name

MK-4827

Synonyms

1038915-60-4; (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide; UNII-HMC2H89N35; HMC2H89N35; CHEMBL1094636; 2-{4-[(3s)-piperidin-3-yl]phenyl}-2h-indazole-7-carboxamide; MK4827; MK 4827; Niraparib [USAN:INN]; 2-{4-[(3S)-piperidin-3-yl]phenyl}indazole-7-carboxamide; 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide; MK 4827 (Base); Niraparib (USAN); Zejula (TN); MK-4827(Niraparib); SCHEMBL1421875; GTPL8275; CTK8B9123; EX-A290; DTXSID50146129; MolPort-023-219-142; ZINC43206370; BDBM50316226

Indication

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 3	[1]
Breast cancer	2C60-2C65	Phase 2	[2]
Ewing sarcoma	2B52	Phase 1	[2]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

320.4

Topological Polar Surface Area (xlogp)

2.2

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Clearance: The total clearance of drug is 16.2 L/h [3]
Half-life: The concentration or amount of drug in body reduced by one-half in 36 hours [4]
Metabolism: The drug is metabolized via the carboxylesterases (CEs) to form a major inactive metabolite [5]
Vd: The volume of distribution (Vd) of drug is 1220 L [3]

Chemical Identifiers

Formula: C19H20N4O
IUPAC Name: 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide
Canonical SMILES: C1C[C@H](CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)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
InChIKey: PCHKPVIQAHNQLW-CQSZACIVSA-N

Cross-matching ID

PubChem CID: 24958200
CAS Number: 1038915-60-4
DrugBank ID: DB11793
TTD ID: D00BMF
INTEDE ID: DR1164
ACDINA ID: D00471

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Poly [ADP-ribose] polymerase (PARP)	TTEBCY8	NOUNIPROTAC	Modulator	[6]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Substrate	[7]
Carboxylesterase 1 (CES1)_{Main DME}	DEB30C5	EST1_HUMAN	Substrate	[8]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Substrate	[8]

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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from MK-4827 (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Gilteritinib	DMWQ4MZ	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Gilteritinib.	Acute myeloid leukaemia [2A60]	[37]
Ag-221	DMS0ZBI	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Ag-221.	BCR-ABL1-negative chronic myeloid leukaemia [2A41]	[37]
Erdafitinib	DMI782S	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Erdafitinib.	Bladder cancer [2C94]	[38]
PF-04449913	DMSB068	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by PF-04449913.	Chronic myelomonocytic leukaemia [2A40]	[39]
Tazemetostat	DMWP1BH	Moderate	Increased risk of bleeding by the combination of MK-4827 and Tazemetostat.	Follicular lymphoma [2A80]	[39]
Arry-162	DM1P6FR	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Arry-162.	Melanoma [2C30]	[37]
Ubrogepant	DM749I3	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Ubrogepant.	Migraine [8A80]	[40]
Rimegepant	DMHOAUG	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Rimegepant.	Migraine [8A80]	[41]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of MK-4827 and Siponimod.	Multiple sclerosis [8A40]	[37]
Ocrelizumab	DMEZ2KH	Moderate	Additive immunosuppressive effects by the combination of MK-4827 and Ocrelizumab.	Multiple sclerosis [8A40]	[42]
Darolutamide	DMV7YFT	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Darolutamide.	Prostate cancer [2C82]	[43]
Tedizolid	DMG2SKR	Moderate	Decreased clearance of MK-4827 due to the transporter inhibition by Tedizolid.	Skin and skin-structure infection [1F28-1G0Z]	[39]
Betrixaban	DM2C4RF	Moderate	Increased risk of bleeding by the combination of MK-4827 and Betrixaban.	Venous thromboembolism [BD72]	[39]
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⏷ Show the Full List of 13 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Erythrosine sodium anhydrous	E00324	27872	Colorant
FD&C blue no. 1	E00263	19700	Colorant
FD&C yellow no. 5 free acid	E00246	16014	Colorant
Hydrazine yellow	E00409	164825	Colorant
Isopropyl alcohol	E00070	3776	Antimicrobial preservative; Solvent
Ammonia	E00007	222	Alkalizing agent
Butyl alcohol	E00011	263	Flavoring agent; Solvent
Ethanol	E00023	702	Antimicrobial preservative; Penetration agent; Solvent
Ferric oxide black	E00522	16211978	Colorant
Gelatin	E00630	Not Available	Other agent
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Potassium hydroxide	E00233	14797	Alkalizing agent
Propylene glycol	E00040	1030	Antimicrobial preservative; Humectant; Plasticizing agent; Solvent
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Water	E00035	962	Solvent
Shellac	E00695	Not Available	Coating agent; Film/membrane-forming agent; Microencapsulating agent; Modified-release agent
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⏷ Show the Full List of 17 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Niraparib 100 mg capsule	100 mg	Oral Capsule	Oral
Niraparib Tosylate 100mg capsule	100mg	Capsule	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	ClinicalTrials.gov (NCT03602859) A Phase 3 Comparison of Platinum-based Therapy With TSR-042 and Niraparib Versus Standard of Care (SOC) Platinum-based Therapy as First-line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST). U.S. National Institutes of Health.
2	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
3	An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
4	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
5	FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
6	Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
7	Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.
8	Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
9	Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitutions on steroid hydroxylase specificity. Pharmacogenetics. 2000 Aug;10(6):519-30.
10	Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
11	Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007 Jul;56(7):887-94.
12	Preferred orientations in the binding of 4'-hydroxyacetanilide (acetaminophen) to cytochrome P450 1A1 and 2B1 isoforms as determined by 13C- and 15N-NMR relaxation studies. J Med Chem. 1994 Mar 18;37(6):860-7.
13	The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
14	Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
15	A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio. Clin Chem Lab Med. 2005;43(7):702-6.
16	Cytochromes P450 in crustacea. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Nov;121(1-3):157-72.
17	Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone. Biochem J. 1998 Apr 1;331 ( Pt 1):273-81.
18	Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab. 2007 Aug;8(6):554-62.
19	Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives. Biomed Chromatogr. 2010 Jan;24(1):104-23.
20	Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models. Biopharm Drug Dispos. 2015 Sep;36(6):385-397.
21	Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013 Nov;41(11):1888-95.
22	Effect of carboxylesterase 1 c.428G>A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Br J Clin Pharmacol. 2015 Nov;80(5):1131-8.
23	Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther. 2004 Aug;310(2):469-76.
24	Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47.
25	Investigation of the metabolism of rufinamide and its interaction with valproate. Drug Metab Lett. 2011 Dec;5(4):280-9.
26	Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder. Neuropsychiatr Dis Treat. 2006 Dec;2(4):467-73.
27	Pharmacogenomics of novel direct oral anticoagulants: newly identified genes and genetic variants. J Pers Med. 2019 Jan 17;9(1). pii: E7.
28	Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704.
29	MFN human ref: Chondroitin sulfate degradation.
30	Foreign Compound Metabolism in Mammals. Edited by D. E. Hathway.
31	2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
32	2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.
33	2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
34	Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res. 2012 Mar 15;18(6):1655-62.
35	Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size. Shock. 2010 May;33(5):507-12.
36	BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases. Mol Cell Biochem. 2012 Jun;365(1-2):129-37.
37	Cerner Multum, Inc. "Australian Product Information.".
38	Product Information. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.
39	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
40	Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
41	Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
42	Product Information. Ocrevus (ocrelizumab). Genentech, South San Francisco, CA.
43	Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.