Nirogacestat is a synthetic gamma-secretase inhibitor and an orally active small-molecule pharmaceutical ingredient. It inhibits gamma-secretase, an enzyme complex involved in the proteolytic processing of several transmembrane proteins, including the Notch receptor.
Nirogacestat is used as an active pharmaceutical ingredient in the development and manufacture of targeted oncology medicines, particularly for progressing desmoid tumors requiring systemic treatment. The marketed pharmaceutical form is nirogacestat hydrobromide (dihydrobromide). (dailymed.nlm.nih.gov)
Nirogacestat is a specialized oncology pharmaceutical API used for gamma-secretase inhibition research, pharmaceutical formulation development and manufacture of targeted anticancer medicines.
The free base and pharmaceutical hydrobromide salt should be distinguished when preparing API documentation. FDA identifies the active ingredient in OGSIVEO as nirogacestat hydrobromide, while FDA's substance database separately identifies the free-base nirogacestat. (precision.fda.gov)
CAS Number — Nirogacestat: 1290543-63-3
CAS Number — Nirogacestat Hydrobromide: 1962925-29-6
Molecular Formula — Nirogacestat: C₂₇H₄₁F₂N₅O
Molecular Weight — Nirogacestat: 489.64 g/mol
Molecular Formula — Nirogacestat Hydrobromide: C₂₇H₄₃Br₂F₂N₅O
Molecular Weight — Nirogacestat Hydrobromide: 651.48 g/mol
Chemical Name: (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide dihydrobromide
Drug Class: Gamma-Secretase Inhibitor
Therapeutic Class: Antineoplastic Agent
Therapeutic Area: Oncology
Molecule Type: Synthetic Small Molecule
Development Code: PF-03084014 / PF-3084014
Target: Gamma-Secretase
FDA and PubChem identify the free base as C₂₇H₄₁F₂N₅O with molecular weight approximately 489.6 g/mol, while FDA/DailyMed identifies the hydrobromide form used in OGSIVEO as C₂₇H₄₃Br₂F₂N₅O with molecular weight 651.48 g/mol. (pubchem.ncbi.nlm.nih.gov)
Nirogacestat inhibits the gamma-secretase enzyme complex, thereby preventing cleavage and activation of Notch receptors.
Its mechanism includes:
The NCI identifies nirogacestat as a gamma-secretase inhibitor that blocks proteolytic activation of the Notch receptor. (cancer.gov)
Nirogacestat API is relevant to:
Nirogacestat is indicated for adult patients with progressing desmoid tumors who require systemic treatment. Desmoid tumors are locally aggressive soft-tissue tumors associated with dysregulated cellular signaling.
Its therapeutic activity is associated with inhibition of gamma-secretase and subsequent reduction of Notch pathway signaling. (cancer.gov)
The Notch signaling pathway regulates processes including cellular differentiation, proliferation and tissue development.
Gamma-secretase participates in the proteolytic activation of Notch receptors. By inhibiting gamma-secretase, Nirogacestat interferes with Notch signaling and downstream biological processes relevant to desmoid tumor growth.
Nirogacestat hydrobromide is described as a white to off-white powder. FDA/DailyMed reports a molecular weight of 651.48 g/mol for the dihydrobromide salt. (dailymed.nlm.nih.gov)
Nirogacestat hydrobromide has an aqueous solubility of approximately 11.4 mg/mL at 25°C, with a measured aqueous solution pH of approximately 4.4. FDA/DailyMed notes that the dihydrobromide salt is highly soluble at low pH, while its solubility decreases substantially at pH values above 6.0. (dailymed.nlm.nih.gov)
Nirogacestat hydrobromide has reported pKa values of approximately:
These values help explain the pH-dependent aqueous solubility of the compound. (dailymed.nlm.nih.gov)
A controlled Nirogacestat API manufacturing process may involve:
Typical Nirogacestat Hydrobromide API testing may include:
| Parameter | Specification |
|---|---|
| Appearance | White crystalline powder or crystals |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Loss on Drying | NMT 1.0% |
| Residue on Ignition | NMT 0.5% |
| Individual Impurity | NMT 0.5% |
| Total Impurities | NMT 1.0% |
| Water Content | NMT 1.0% |
| Solubility | 11.4 mg/mL in water at 25°C for Nirogacestat Hydrobromide |