NIROGACESTAT HYDROBROMIDE

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 Search

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
Sources: http://adisinsight.springer.com/drugs/800025563
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Gamma-secretase 21 Target ID: CHEMBL2094135 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20363853	Inhibitor 8297		1.2 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Aggressive Fibromatosis 2 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1132	Unknown Approved Use Unknown
Pancreatic cancer 97 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1132	Unknown Approved Use Unknown
Breast cancer 434 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
963 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27906684	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62	DLT: Diarrhea... Dose limiting toxicities: Diarrhea (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/25231399 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 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: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1737 inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 CYP3A 214 P-gp 1461	CYPs 33 rP-gp 2

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363678166	inconclusive [IC50 8.1995 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 13.5 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 18.5 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 20.3 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [Ki 2.2 uM]
CYP3A 298	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	yes [IC50 4.6 uM]	yes (co-administration study) Comment: Increased midazolam AUCinf and Cmax by 58.9% and 30.7% Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0
CYP3A4 1925	inducer 1573 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	yes
P-gp 1650	supressor 155 Sources: https://pubmed.ncbi.nlm.nih.gov/26202948/	yes

Drug as victim

Target	Modality	Activity
CYPs 33	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23427934/	likely
rP-gp 2	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	no
CYP3A4 1737	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=10 Page: 10.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=11 Page: 11.0

PubMed

Title	Date	PubMed
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.	2010 Jun	20530712
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	21269827
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.	2011 Nov 24	21995460
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.	2015 Jan	24781018
Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.	2015 Nov 15	26349011

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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 UTC 2023` Edited by `admin` on `Sat Dec 16 14:45:26 UTC 2023`
Record UNII	9T1XY6L45Y
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NIROGACESTAT HYDROBROMIDE

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