U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C27H41F2N5O.2BrH
Molecular Weight 651.468
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NIROGACESTAT HYDROBROMIDE

SMILES

Br.Br.CCC[C@H](N[C@H]1CCC2=C(C1)C(F)=CC(F)=C2)C(=O)NC3=CN(C=N3)C(C)(C)CNCC(C)(C)C

InChI

InChIKey=LXEYYZYDWLAIPW-KBVFCZPLSA-N
InChI=1S/C27H41F2N5O.2BrH/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4;;/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35);2*1H/t20-,23-;;/m0../s1

HIDE SMILES / InChI

Molecular Formula BrH
Molecular Weight 80.912
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C27H41F2N5O
Molecular Weight 489.6441
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20363853 | https://www.ncbi.nlm.nih.gov/pubmed/24919951 | https://www.ncbi.nlm.nih.gov/pubmed/21269827

Nirogacestat (PF-3084014) is a tetralin imidazole gamma-secretase inhibitor. Gamma-secretase, a proteolytic enzyme complex, mediates processing of several integral membrane proteins including amyloid precursor protein and Notch. This compound can inhibit both Notch-related pathway in neoplasia and reduces amyloid-β production. Nirogacestat (PF-3084014) is under development by Pfizer for the treatment of cancer.

CNS Activity

Curator's Comment: Nirogacestat (PF-3084014) is neuroactive in the rodent brain. No human data available.

Originator

Curator's Comment: # Pfizer

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
1.2 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
963 ng/mL
100 mg 2 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
NIROGACESTAT plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
330 mg 2 times / day multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / day
Route: oral
Route: multiple
Dose: 330 mg, 2 times / day
Sources: Page: p.62
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources: Page: p.62
DLT: Skin rash...
Disc. AE: Palpitations, Oropharyngeal pain...
Dose limiting toxicities:
Skin rash (grade 3, 50%)
AEs leading to
discontinuation/dose reduction:
Palpitations (grade 1, 50%)
Oropharyngeal pain (grade 1, 50%)
Sources: Page: p.62
220 mg 2 times / day multiple, oral
MTD
Dose: 220 mg, 2 times / day
Route: oral
Route: multiple
Dose: 220 mg, 2 times / day
Sources: Page: p.62
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.62
DLT: Diarrhea...
Dose limiting toxicities:
Diarrhea (grade 3, 16.7%)
Sources: Page: p.62
150 mg 2 times / day multiple, oral
Studied dose
Dose: 150 mg, 2 times / day
Route: oral
Route: multiple
Dose: 150 mg, 2 times / day
Sources: Page: p.1565
unhealthy, ADULT
n = 17
Health Status: unhealthy
Condition: desmoid tumor
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 17
Sources: Page: p.1565
Disc. AE: Maculopapular rash, Nausea...
AEs leading to
discontinuation/dose reduction:
Maculopapular rash (grade 2, 5.9%)
Nausea (grade 2, 5.9%)
Diarrhea (grade 2, 5.9%)
Allergic urticaria (5.9%)
Sources: Page: p.1565
AEs

AEs

AESignificanceDosePopulation
Oropharyngeal pain grade 1, 50%
Disc. AE
330 mg 2 times / day multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / day
Route: oral
Route: multiple
Dose: 330 mg, 2 times / day
Sources: Page: p.62
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources: Page: p.62
Palpitations grade 1, 50%
Disc. AE
330 mg 2 times / day multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / day
Route: oral
Route: multiple
Dose: 330 mg, 2 times / day
Sources: Page: p.62
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources: Page: p.62
Skin rash grade 3, 50%
DLT
330 mg 2 times / day multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / day
Route: oral
Route: multiple
Dose: 330 mg, 2 times / day
Sources: Page: p.62
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources: Page: p.62
Diarrhea grade 3, 16.7%
DLT
220 mg 2 times / day multiple, oral
MTD
Dose: 220 mg, 2 times / day
Route: oral
Route: multiple
Dose: 220 mg, 2 times / day
Sources: Page: p.62
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.62
Allergic urticaria 5.9%
Disc. AE
150 mg 2 times / day multiple, oral
Studied dose
Dose: 150 mg, 2 times / day
Route: oral
Route: multiple
Dose: 150 mg, 2 times / day
Sources: Page: p.1565
unhealthy, ADULT
n = 17
Health Status: unhealthy
Condition: desmoid tumor
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 17
Sources: Page: p.1565
Diarrhea grade 2, 5.9%
Disc. AE
150 mg 2 times / day multiple, oral
Studied dose
Dose: 150 mg, 2 times / day
Route: oral
Route: multiple
Dose: 150 mg, 2 times / day
Sources: Page: p.1565
unhealthy, ADULT
n = 17
Health Status: unhealthy
Condition: desmoid tumor
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 17
Sources: Page: p.1565
Maculopapular rash grade 2, 5.9%
Disc. AE
150 mg 2 times / day multiple, oral
Studied dose
Dose: 150 mg, 2 times / day
Route: oral
Route: multiple
Dose: 150 mg, 2 times / day
Sources: Page: p.1565
unhealthy, ADULT
n = 17
Health Status: unhealthy
Condition: desmoid tumor
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 17
Sources: Page: p.1565
Nausea grade 2, 5.9%
Disc. AE
150 mg 2 times / day multiple, oral
Studied dose
Dose: 150 mg, 2 times / day
Route: oral
Route: multiple
Dose: 150 mg, 2 times / day
Sources: Page: p.1565
unhealthy, ADULT
n = 17
Health Status: unhealthy
Condition: desmoid tumor
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 17
Sources: Page: p.1565
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer






Drug as perpetrator​Drug as victimTox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.
2010 Jul
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.
2011 Nov 24
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
2015 Jan
Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer.
2015 Oct 15
Patents

Patents

Sample Use Guides

Dosage of Nirogacestat (PF-3084014) in phase II trial in adults with desmoid tumors/aggressive fibromatosis: orally at 150 mg twice a day in 21-day cycles
Route of Administration: Oral
Nirogacestat (PF-3084014) can block Nicastrin/Notch4 axis and reverse epithelial to mesenchymal transition process in in MCF7 breast cancer cells.
Substance Class Chemical
Created
by admin
on Sat Dec 16 14:45:26 GMT 2023
Edited
by admin
on Sat Dec 16 14:45:26 GMT 2023
Record UNII
9T1XY6L45Y
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NIROGACESTAT HYDROBROMIDE
USAN  
Official Name English
(2S)-2-{[(2S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino}-N-(1-{1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl}-1H-imidazol-4-yl)pentanamide dihydrobromide
Systematic Name English
PENTANAMIDE, 2-(((2S)-6,8-DIFLUORO-1,2,3,4-TETRAHYDRO-2-NAPHTHALENYL)AMINO)-N-(1-(2-((2,2-DIMETHYLPROPYL)AMINO)-1,1-DIMETHYLETHYL)-1H-IMIDAZOL-4-YL)-, HYDROBROMIDE (1:2), (2S)-
Systematic Name English
PF-03084014-04
Code English
NIROGACESTAT DIHYDROBROMIDE
Common Name English
OGSIVEO
Brand Name English
NIROGACESTAT HYDROBROMIDE [USAN]
Common Name English
Code System Code Type Description
PUBCHEM
121513889
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
FDA UNII
9T1XY6L45Y
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
NCI_THESAURUS
C174588
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
EVMPD
SUB197065
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
CAS
1962925-29-6
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
SMS_ID
100000182765
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
USAN
GH-54
Created by admin on Sat Dec 16 14:45:27 GMT 2023 , Edited by admin on Sat Dec 16 14:45:27 GMT 2023
PRIMARY
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