Niraparib

Product Overview

Niraparib (development code MK-4827) was developed by Tesaro (later acquired by GSK) and marketed as Zejula; ATC code L01XK02; approved by the US FDA on March 27, 2017.

Structural class: The molecule is built on a 2H-indazole-7-carboxamide scaffold—position 2 of the indazole (N2) is linked to a para-substituted phenyl group, which in turn carries a (3S)-piperidin-3-yl group at its para position; position 7 of the indazole bears the carboxamide. This structure mimics the nicotinamide portion of nicotinamide adenine dinucleotide (NAD⁺) and competes for the NAD⁺-binding pocket of the PARP catalytic domain.

Mechanism of action (“synthetic lethality”): PARP (especially PARP1) is a key enzyme in DNA single-strand break repair (the base excision repair pathway). After niraparib inhibits PARP, unrepaired single-strand breaks are converted into double-strand breaks at DNA replication forks. Normal cells can repair double-strand breaks via homologous recombination repair (HR), whereas tumor cells carrying BRCA1/2 mutations or other homologous recombination repair deficiencies (HRD) lack this capability; double-strand breaks continue to accumulate, ultimately leading to apoptosis—this is the “synthetic lethality” effect. In addition, PARP inhibition stabilizes PARP binding at DNA damage sites, forming “PARP trapping” complexes that further impede replication fork progression.

Potency: IC50 values against PARP1 and PARP2 are approximately 3.8 nM and 2.1 nM, respectively, with high potency and oral bioavailability.

Salt form note: The active ingredient of the marketed formulation Zejula is the free base, but its stable form is the crystalline hydrate of the tosylate salt (niraparib tosylate monohydrate) or the hydrochloride (niraparib hydrochloride)—CAS 1038915-60-4 in this entry corresponds to the free base, which is a different substance from the tosylate monohydrate; pay attention to molecular weight differences in procurement and formulation conversion.

Technical Specifications

• Standards: CHP/USP/EP

• Specification: 0.99 (purity ≥99.0%, HPLC); reagent grade commonly ≥98%

• CAS Number: 1038915-60-4 (free base, UNII HMC2H89N35, ATC L01XK02, MDL MFCD17779309); the tosylate monohydrate used in the marketed formulation has a different CAS number—the free base and the salt form must not be used interchangeably

• Molecular Formula: C₁₉H₂₀N₄O

• Molecular Weight: 320.39 (consistent across CAS Common Chemistry, ChemicalBook, and Viva Supply); other calculated values 320.388/320.3883

• Appearance: Off-white to pale yellow/light yellow (Pale Yellow to Light Yellow) crystalline solid or powder; some suppliers describe it as a white to pale yellow crystalline powder, others as a white to brown solid

• Purity (HPLC): ≥ 99.0%

• Melting Point: 187–189 ℃ (consistent across multiple sources including ChemicalBook, Guidechem, Viva Supply, and Mordor Chemistry; recommended). The above values come from literature/supplier standards; no publicly accessible official pharmacopoeial melting point has been found

• Specific Rotation: The molecule contains 1 defined stereocenter ((3S)-piperidin-3-yl; PubChem records Defined Atom Stereocenter Count = 1); no publicly accessible official pharmacopoeial specific rotation has been found; quality control is typically achieved through chiral HPLC/enantiomeric purity and structural confirmation (NMR, MS)

• Chemical Name: 2-[4-((3S)-3-Piperidinyl)phenyl]-2H-indazole-7-carboxamide; IUPAC: (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

• Stereochemistry: Single (3S) configuration, 1 defined stereocenter

• Solubility: Slightly/sparingly soluble in DMSO (about 25–64 mg/mL, sonication required); soluble in ethanol (about 64 mg/mL); slightly soluble in methanol; insoluble in water

• Acidity Coefficient (pKa): 15.36 ± 0.30 (calculated value)

• Calculated Physicochemical Parameters: Density about 1.34 g/cm³ (CAS-derived calculated value 1.343 ± 0.14); boiling point about 463.6 ± 45.0 ℃ (calculated); flash point about 234.2 ℃; LogP about 3.62 (also recorded as 3.8)

• Marketed Formulation Strength: Capsules, 100 mg (calculated as niraparib; actually the tosylate monohydrate)

• Storage: Store at 2–8 ℃ protected from light; some sources recommend −20 ℃ protected from light; solutions should be aliquoted and stored at low temperature, avoiding repeated freeze-thaw cycles

Applications

• Maintenance treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (core indication): For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved complete or partial response to platinum-based chemotherapy. Approved by the FDA on March 27, 2017

• Mechanism-related research: Used for PARP1/PARP2 inhibitory activity evaluation, PARP trapping studies, synthetic lethality research in the context of homologous recombination repair deficiency (HRD) and BRCA1/2 mutations, DNA damage repair pathway studies (base excision repair, replication fork stability), and apoptosis induction research

• Combination therapy and indication-expansion research: Exploration of combinations with anti-angiogenic agents, immune checkpoint inhibitors, and chemoradiotherapy; expansion studies in solid tumors harboring HRD/BRCA mutations such as breast, pancreatic, and prostate cancers—the above are mostly investigational directions; specific approved indications are subject to the latest local labels

• Formulation and manufacturing: Used for formulation development of capsules (100 mg) and tablets; the API is insoluble in water, so formulations must address solubilization and dissolution; key manufacturing control points include chiral purity ((3S) enantiomer), related substances (especially indazole N-alkylation isomers and piperidine-related impurities), assay, crystal form, and residual solvents; suitable for analytical method development and validation, stability studies, impurity reference standards, and GMP scale-up and CMO/CDMO contract manufacturing

Safety Notice: This product is a pharmaceutical active ingredient (API) intended solely for compliant industrial, research, and pharmaceutical manufacturing use; it is not intended for end clinical use or self-medication guidance. The finished product is a prescription drug and must be prescribed by physicians experienced in antineoplastic therapy with regular monitoring. Key warnings: ① Myelosuppression—thrombocytopenia, anemia, and neutropenia are common and can lead to serious or even fatal events; complete blood counts should be monitored weekly during the first month of treatment and monthly thereafter, with dose adjustment or treatment interruption according to adverse reactions; ② Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)—has been reported and can be fatal; evaluate when prolonged hematologic toxicity occurs; ③ Hypertension and cardiovascular events—hypertensive crisis may occur; monitor blood pressure and heart rate monthly during the first year of treatment and periodically thereafter; ④ Posterior reversible encephalopathy syndrome (PRES)—rare but potentially fatal; evaluate immediately and discontinue if seizures, headache, visual disturbances, or altered consciousness occur; ⑤ Embryo-fetal toxicity—can cause fetal harm; females of reproductive potential must use effective contraception during treatment and for a period after the last dose; ⑥ Gastrointestinal reactions (nausea, vomiting, constipation, decreased appetite), fatigue, and elevated liver enzymes are also common. The API is GHS-classified as Acute Oral Toxicity Category 4, Skin Irritation Category 2, Serious Eye Irritation Category 2, Acute Inhalation Toxicity Category 4, and Specific Target Organ Toxicity (single exposure, respiratory irritation) Category 3 (H302/H315/H319/H332/H335); wear protective gloves, protective clothing, and respiratory and eye/face protection during handling, and avoid dust inhalation.

Product information: please contact us. This information is for reference only.