Itareparib

CAS 1606995-47-4

MF C20H26FN3O2 MW359.4 g/mol

2-(1-Cyclohexyl-4-piperidinyl)-6-fluoro-2,3-dihydro-3-oxo-1H-isoindole-4-carboxamide

1H-ISOINDOLE-4-CARBOXAMIDE, 2-(1-CYCLOHEXYL-4-PIPERIDINYL)-6-FLUORO-2,3-DIHYDRO-3-OXO-

2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole4-carboxamide
poly (ADP-ribose) polymerase (PARP) inhibitor, antineoplastic, NMS-03305293, NMS-293, NMS 03305293, NMS 293, KFI1190L8L, NV 578,

Itareparib is the inhibitor for PARP and exhibits antineoplastic activity.

Itareparib (development code NMS-03305293 or NMS-293) is an experimental, next-generation PARP1-selective oral inhibitor being developed by the biopharmaceutical company Nerviano Medical Sciences for the treatment of various advanced solid tumors and brain cancers

Key Characteristics & Mechanism

Unlike first-generation poly(ADP-ribose) polymerase (PARP) inhibitors, itareparib features a highly specialized mechanism designed to improve clinical safety and versatility:

• Non-Trapping Profile: Traditional PARP inhibitors trap the PARP enzyme onto DNA, forming PARP-DNA complexes. This trapping causes significant bone marrow toxicity (myelosuppression), leading to severe side effects like anemia, neutropenia, and thrombocytopenia. Itareparib is engineered to be “non-trapping,” avoiding these complexes to protect healthy blood cells.
• High Brain Penetrance: It crosses the blood-brain barrier effectively, making it uniquely suitable for treating primary and secondary central nervous system (CNS) malignancies.
• Ideal Combinability: Because it does not cause overlapping bone marrow toxicity, it can be safely paired with other DNA-damaging therapies like traditional chemotherapies and antibody-drug conjugates (ADCs).

Clinical Development & Target Indications

Itareparib is currently advancing through Phase I and Phase II clinical trials. It is being investigated across several oncology settings:

• Glioblastoma (GBM): Evaluated in Phase II clinical studies for relapsed, IDH wild-type glioblastoma in combination with the chemotherapy drug temozolomide (TMZ).
• Ovarian Cancer: Evaluated in Phase Ia/Ib trials (such as trial NCT06930755) in combination with topotecan for patients with recurrent, platinum-resistant ovarian, fallopian tube, or peritoneal cancers. [1]
• Small Cell Lung Cancer (SCLC) & Astrocytoma: Explored in ongoing combination trials targeting highly aggressive tumors where conventional PARP inhibitors are limited by overlapping toxicity.

• Study of NMS-03305293 in Adult Patients With Relapsed Ovarian CancerCTID: NCT06930755Phase: Phase 1Status: RecruitingDate: 2026-05-28
• Study of NMS-03305293 in Adult Patient With Relapsed Small Cell Lung CancerCTID: NCT06931626Phase: Phase 1Status: RecruitingDate: 2025-11-12
• Ph I/II Study of NMS-03305293+TMZ in Adult Patients With Recurrent GlioblastomaCTID: NCT04910022Phase: Phase 1/Phase 2Status: Active, not recruitingDate: 2025-08-19
• Study of NMS-03305293 in Pts with Selected Advanced/Metastatic Solid TumorsCTID: NCT04182516Phase: Phase 1Status: TerminatedDate: 2024-09-19

A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients with Recurrent Glioblastoma

EudraCT: 2020-003417-35

Phase: Phase 1, Phase 2

Status: Trial now transitioned

Date: 2021-11-10

SYN

US10800739,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481284&_cid=P10-MQA9O8-42416-1

2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oz-2,3-dihydro-1H-isoindole-4-carboxylic Acid Amide (I), cpd 29 [R═F; n=m=0; R1=piperidin-4-yl; R2=1-cyclohexyl]

To a stirred solution of 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) (100 mg, 0.3 mmol) in acetic acid (5 mL), concentrated sulfuric acid (2.7 mL) was added dropwise during 30 min. The reaction was then warmed at 80° C. for 9 h, cooled at room temperature and poured into cold water (10 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2×12 mL) and brine, dried over Na 2SO 4 and evaporated to dryness in vacuo. The title compound was obtained as a white solid (43 mg, 40%) after purification through column chromatography ((dichloromethane/methanol/ammonia solution, 7N in methanol:97/2/1).

1H NMR (400.5 MHz, DMSO-d 6) δ ppm 1.00-1.14 (m, 1H), 1.14-1.28 (m, 4H), 1.53-1.61 (m, 1H), 1.67-1.80 (m, 6H), 2.25-2.36 (m, 3H), 2.88-2.95 (m, 2H), 3.94-4.03 (m, 1H), 4.55 (s, 2H), 7.66 (dd, J HF=7.7, J HH=2.6 Hz, 1H), 7.85 (br. s., 1H), 7.89 (dd, J HF=10.9, J HH=2.6 Hz, 1H), 10.78 (br. s., 1H).

HRMS (ESI+): calcd. for C 20H 27FN 32 [M+H] + 3602082: found 360.2098.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014064149&_cid=P10-MQA9K8-39764-1

2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxylic acid amide (I), cpd 29

[R = F; n = m = 0; R1 = piperidin-4-yl; R2 = 1-cyclohexyl]

To a stirred solution of 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carbonitrile (IV) (100 mg, 0.3 mmol) in acetic acid (5 mL), concentrated sulfuric acid (2.7 mL) was added dropwise during 30 min. The reaction was then warmed at 80 °C for 9 h, cooled at room temperature and poured into cold water (10 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2 X 12 mL) and brine, dried over Na2S04 and evaporated to dryness in vacuo. The title compound was obtained as a white solid (43 mg, 40%) after purification through column chromatography ((dichloromethane/methanol/ammonia solution, 7N in methanol: 97/2/1).

¹H NMR (400.5 MHz, DMSO- cfe) δ ppm 1.00 – 1.14 (m, 1 H), 1.14 – 1.28 (m, 4 H), 1.53 – 1.61 (m, 1 H), 1.67 – 1.80 (m, 6 H), 2.25 – 2.36 (m, 3 H), 2.88 – 2.95 (m, 2 H), 3.94 – 4.03 (m, 1 H), 4.55 (s, 2 H), 7.66 (dd, JHF = 7.7, JHH = 2.6 Hz, 1 H), 7.85 (br. s., 1 H), 7.89 (dd, JHF = 10.9, JHH = 2.6 Hz, 1 H), 10.78 (br. s., 1 H).

HRMS (ESI+): calcd. for C20H27FN3O2 [M + H]⁺ 360.2082; found 360.2098

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////////itareparib, ANAX LABS, poly (ADP-ribose) polymerase (PARP) inhibitor, antineoplastic, NMS-03305293, NMS-293, NMS 03305293, NMS 293, KFI1190L8L, NV 578,