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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
Structure of AVAGACESTAT

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

HIDE SMILES / InChI

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

Description
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

Curator's Comment: Avagacestat (BMS-708163) can cross the blood-brain barrier and is efficacious in the treatment of AD.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
3001 ng/mL
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

AUC

ValueDoseCo-administeredAnalytePopulation
36671 ng × h/mL
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

T1/2

ValueDoseCo-administeredAnalytePopulation
41 h
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

Doses

DosePopulationAdverse 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%)
Dysacusis (16.7%)
Dysacusis (33.3%)
Sources: Page: p.660
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%)
Skin disorder (15%)
Sources: Page: p.1434
AEs

AEs

AESignificanceDosePopulation
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
PubMed

PubMed

TitleDatePubMed
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
ACS chemical neuroscience molecule spotlight on BMS-708163.
2012 Mar 21
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
Patents

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
Avagacestat (BMS-708163) inhibited gamma-secretase in human IMR32 cell membrane with IC50 0.13 nM
Substance Class Chemical
Created
by admin
on Thu Jul 06 01:57:37 UTC 2023
Edited
by admin
on Thu Jul 06 01:57:37 UTC 2023
Record UNII
TQ44WWY45Q
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
AVAGACESTAT
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
AVAGACESTAT [USAN]
Common Name English
BMS-708163-01
Code English
(2R)-2-(N-((4-CHLOROPHENYL)SULFONYL)-N-((2-FLUORO-4-(1,2,4-OXADIAZOL-3-YL)PHENYL)METHYL)AMINO)-5,5,5-TRIFLUOROPENTANAMIDE
Systematic Name English
BMS-708163
Code English
PENTANAMIDE, 2-(((4-CHLOROPHENYL)SULFONYL)((2-FLUORO-4-(1,2,4-OXADIAZOL-3-YL)PHENYL)METHYL)AMINO)-5,5,5-TRIFLUORO-, (2R)-
Systematic Name English
avagacestat [INN]
Common Name English
BMS-70816301
Code English
Avagacestat [WHO-DD]
Common Name English
BMS708163
Code English
Classification Tree Code System Code
NCI_THESAURUS C783
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
Code System Code Type Description
USAN
XX-31
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
SMS_ID
300000034161
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
PUBCHEM
46883536
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
DRUG BANK
DB11893
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
FDA UNII
TQ44WWY45Q
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
INN
9351
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
ChEMBL
CHEMBL1090771
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
CAS
1146699-66-2
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
NCI_THESAURUS
C96305
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
EPA CompTox
DTXSID40150811
Created by admin on Thu Jul 06 01:57:37 UTC 2023 , Edited by admin on Thu Jul 06 01:57:37 UTC 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
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ACTIVE MOIETY