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
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
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 |
DescriptionSources: http://adisinsight.springer.com/drugs/800025563Curator'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
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21269827 | https://www.ncbi.nlm.nih.gov/pubmed/20363853
Curator's Comment: Nirogacestat (PF-3084014) is neuroactive in the rodent brain. No human data available.
Originator
Sources: http://adisinsight.springer.com/drugs/800025563
Curator's Comment: # Pfizer
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2094135 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20363853 |
1.2 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
Cmax
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: 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 todiscontinuation/dose reduction: Palpitations (grade 1, 50%) Sources: Page: p.62Oropharyngeal pain (grade 1, 50%) |
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%) Sources: Page: p.1565Nausea (grade 2, 5.9%) Diarrhea (grade 2, 5.9%) Allergic urticaria (5.9%) |
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: 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
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
inconclusive [IC50 8.1995 uM] | ||||
Page: 14.0 |
no | |||
Page: 14.0 |
weak [IC50 13.5 uM] | |||
Page: 14.0 |
weak [IC50 18.5 uM] | |||
Page: 14.0 |
weak [IC50 20.3 uM] | |||
Page: 14.0 |
weak [Ki 2.2 uM] | |||
Page: 14.0 |
yes [IC50 4.6 uM] | yes (co-administration study) Comment: Increased midazolam AUCinf and Cmax by 58.9% and 30.7% Page: 14.0 |
||
Page: 14.0 |
yes | |||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
likely | ||||
Page: 14.0 |
no | |||
Page: 10.0 |
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 11.0 |
PubMed
Title | Date | PubMed |
---|---|---|
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
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01981551
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24919951
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
Edited
Sat Dec 16 14:45:26 GMT 2023
by
admin
on
Sat Dec 16 14:45:26 GMT 2023
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Record UNII |
9T1XY6L45Y
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Record Status |
Validated (UNII)
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Record Version |
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121513889
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9T1XY6L45Y
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C174588
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SUB197065
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1962925-29-6
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100000182765
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GH-54
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ACTIVE MOIETY |
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