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

Details

Stereochemistry ABSOLUTE
Molecular Formula C27H41F2N5O
Molecular Weight 489.6452
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NIROGACESTAT

SMILES

CCC[C@@]([H])(C(=Nc1cn(cn1)C(C)(C)CNCC(C)(C)C)O)N[C@@]2([H])CCc3cc(cc(c3C2)F)F

InChI

InChIKey=VFCRKLWBYMDAED-REWPJTCUSA-N
InChI=1S/C27H41F2N5O/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)/t20-,23-/m0/s1

HIDE SMILES / InChI

Molecular Formula C27H41F2N5O
Molecular Weight 489.6452
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
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.
2010 Jun
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.
2011 May 1
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.
2011 Nov 24
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.
2012 Jul
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.
2012 Sep 15
Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.
2013 Aug 6
Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.
2013 Jul 10
Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.
2014 Aug
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
2015 Jan
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 Jun 26 01:46:50 UTC 2021
Edited
by admin
on Sat Jun 26 01:46:50 UTC 2021
Record UNII
QZ62892OFJ
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NIROGACESTAT
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
PF-03084014
Code English
(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
Systematic Name English
NIROGACESTAT [USAN]
Common Name English
NIROGACESTAT [WHO-DD]
Common 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)-, (2S)-
Systematic Name English
(2S)-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)PENTANAMIDE
Systematic Name English
PF 3084014
Code English
PF 03084014
Code English
NIROGACESTAT [INN]
Common Name English
PF-3084014
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 636518
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
Code System Code Type Description
ChEMBL
CHEMBL1770916
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
EPA CompTox
865773-15-5
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
DRUG BANK
DB12005
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
CAS
1290543-63-3
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
FDA UNII
QZ62892OFJ
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
CAS
865773-15-5
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
NON-SPECIFIC STEREOCHEMISTRY
PUBCHEM
46224413
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
NCI_THESAURUS
C82383
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
INN
10404
Created by admin on Sat Jun 26 01:46:50 UTC 2021 , Edited by admin on Sat Jun 26 01:46:50 UTC 2021
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
FREE ASSAY
REVERSIBLE
IC50
BINDER->LIGAND
BINDING
TRANSPORTER -> SUBSTRATE
METABOLIC ENZYME -> INHIBITOR
IC50
TARGET -> INHIBITOR
Cellular assay using HEK293 cell line is 7.7 nM (0.34 nM free) for notch intracellular domain (NICD) inhibition
IC50
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC