NIROGACESTAT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C27H41F2N5O
Molecular Weight	489.6441
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

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=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	489.6441
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

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	Inhibitor 8,297		1.2 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Aggressive Fibromatosis 2	Primary	Phase II 1,132	Unknown
Pancreatic cancer 97	Primary	Phase II 1,132	Unknown
Breast cancer 434	Primary	Phase II 1,132	Unknown

C_max

C_max

Value	Dose	Co-administered	Analyte	Population
963 ng/mL	100 mg 2 times / day multiple, oral		NIROGACESTAT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
330 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT n = 2	DLT: Skin rash... Disc. AE: Palpitations, Oropharyngeal pain...
220 mg 2 times / day multiple, oral MTD	unhealthy, ADULT n = 6	DLT: Diarrhea...
150 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT n = 17	Disc. AE: Maculopapular rash, Nausea...

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AEs

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AE	Significance	Dose	Population
Oropharyngeal pain	grade 1, 50% Disc. AE	330 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT n = 2
Palpitations	grade 1, 50% Disc. AE	330 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT n = 2
Skin rash	grade 3, 50% DLT	330 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT n = 2
Diarrhea	grade 3, 16.7% DLT	220 mg 2 times / day multiple, oral MTD	unhealthy, ADULT n = 6
Allergic urticaria	5.9% Disc. AE	150 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT n = 17

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1,737 inhibitor 1,587	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2C19 1,478 CYP3A 214 P-gp 1,461	CYPs 33 rP-gp 2

Drug as perpetrator

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Target	Modality	Activity
P-gp 1,650	inhibitor 3,277	inconclusive [IC50 8.1995 uM]
CYP1A2 1,692	inhibitor 3,277	no
CYP2D6 1,891	inhibitor 3,277	weak [IC50 13.5 uM]
CYP2C9 1,819	inhibitor 3,277	weak [IC50 18.5 uM]
CYP2C19 1,553	inhibitor 3,277	weak [IC50 20.3 uM]

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Drug as victim

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Target	Modality	Activity
CYPs 33	substrate 3,367	likely
rP-gp 2	substrate 3,367	no
CYP3A4 1,737	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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PubMed

Title	Date	PubMed
No data available in table

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
Record UNII	QZ62892OFJ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NIROGACESTAT

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

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

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Classification Tree

Code System

Code