Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C20H17ClF4N4O4S |
Molecular Weight | 520.885 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC(=O)[C@@H](CCC(F)(F)F)N(CC1=CC=C(C=C1F)C2=NOC=N2)S(=O)(=O)C3=CC=C(Cl)C=C3
InChI
InChIKey=XEAOPVUAMONVLA-QGZVFWFLSA-N
InChI=1S/C20H17ClF4N4O4S/c21-14-3-5-15(6-4-14)34(31,32)29(17(18(26)30)7-8-20(23,24)25)10-13-2-1-12(9-16(13)22)19-27-11-33-28-19/h1-6,9,11,17H,7-8,10H2,(H2,26,30)/t17-/m1/s1
Molecular Formula | C20H17ClF4N4O4S |
Molecular Weight | 520.885 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/24900185 | https://www.ncbi.nlm.nih.gov/pubmed/22860183
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/24900185 | https://www.ncbi.nlm.nih.gov/pubmed/22860183
Avagacestat (BMS-708163) is an oral gamma secretase inhibitor designed for selective inhibition of amyloid beta (Aβ) synthesis. Avagacestat was in development by Bristol-Myers Squibb for the treatment of Alzheimer's disease (AD). Avagacestat is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch. In November 2012, Bristol-Myers Squibb terminated clinical trials of the drug and announced its decision to end further development of avagacestat
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22931393 | https://www.ncbi.nlm.nih.gov/pubmed/27641902
Curator's Comment: Avagacestat (BMS-708163) can cross the blood-brain barrier and is efficacious in the treatment of AD.
Originator
Sources: http://adisinsight.springer.com/drugs/800028449 | https://www.ncbi.nlm.nih.gov/pubmed/22860183
Curator's Comment: # Bristol-Myers Squibb
Approval Year
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
3001 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22381714 |
800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: |
AVAGACESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
36671 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22381714 |
800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: |
AVAGACESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
41 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22381714 |
800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: |
AVAGACESTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
800 mg single, oral Highest studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: Page: p.660 |
healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: Page: p.660 |
Other AEs: Dizziness, Dysacusis... Other AEs: Dizziness (33.3%) Sources: Page: p.660Dysacusis (16.7%) Dysacusis (33.3%) |
125 mg 1 times / day multiple, oral Studied dose Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.1434 |
unhealthy, ADULT n = 40 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 40 Sources: Page: p.1434 |
Disc. AE: Gastro-intestinal disorder, Skin disorder... AEs leading to discontinuation/dose reduction: Gastro-intestinal disorder (7.5%) Sources: Page: p.1434Skin disorder (15%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Dysacusis | 16.7% | 800 mg single, oral Highest studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: Page: p.660 |
healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: Page: p.660 |
Dizziness | 33.3% | 800 mg single, oral Highest studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: Page: p.660 |
healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: Page: p.660 |
Dysacusis | 33.3% | 800 mg single, oral Highest studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: Page: p.660 |
healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: Page: p.660 |
Skin disorder | 15% Disc. AE |
125 mg 1 times / day multiple, oral Studied dose Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.1434 |
unhealthy, ADULT n = 40 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 40 Sources: Page: p.1434 |
Gastro-intestinal disorder | 7.5% Disc. AE |
125 mg 1 times / day multiple, oral Studied dose Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.1434 |
unhealthy, ADULT n = 40 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 40 Sources: Page: p.1434 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
inconclusive [IC50 7.4266 uM] | ||||
moderate | ||||
no | ||||
no | ||||
no | ||||
weak [IC50 20 uM] | ||||
weak |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
likely | ||||
no | ||||
no |
PubMed
Title | Date | PubMed |
---|---|---|
Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor. | 2010 Jun 10 |
|
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors. | 2011 Nov 24 |
|
Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. | 2012 Nov |
|
BMS-708,163 targets presenilin and lacks notch-sparing activity. | 2012 Sep 18 |
Sample Use Guides
Of the four Avagacestat (BMS-708163) doses evaluated (25 mg, 50 mg, 100 mg and 125 mg/day), doses below 100 mg/day demonstrated acceptable tolerability profiles for further development and were associated with discontinuation rates comparable with placebo. BMS-708163 doses at or above 100 mg were associated with higher discontinuation rates, most commonly due to gastrointestinal and dermatological side effects.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23312944
Avagacestat (BMS-708163) inhibited gamma-secretase in human IMR32 cell membrane with IC50 0.13 nM
Substance Class |
Chemical
Created
by
admin
on
Edited
Fri Dec 15 18:46:27 GMT 2023
by
admin
on
Fri Dec 15 18:46:27 GMT 2023
|
Record UNII |
TQ44WWY45Q
|
Record Status |
Validated (UNII)
|
Record Version |
|
-
Download
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Systematic Name | English | ||
|
Code | English | ||
|
Systematic Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Code | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
NCI_THESAURUS |
C783
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
XX-31
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
300000034161
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
46883536
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
DB11893
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
TQ44WWY45Q
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
9351
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
CHEMBL1090771
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
1146699-66-2
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
C96305
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY | |||
|
DTXSID40150811
Created by
admin on Fri Dec 15 18:46:27 GMT 2023 , Edited by admin on Fri Dec 15 18:46:27 GMT 2023
|
PRIMARY |
Related Record | Type | Details | ||
---|---|---|---|---|
|
TARGET -> INHIBITOR |
|
Related Record | Type | Details | ||
---|---|---|---|---|
|
ACTIVE MOIETY |
|