AVAGACESTAT

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 Search

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
Sources: http://www.alzforum.org/therapeutics/avagacestat | http://www.bms.com/news/features/2012/Pages/AvagacestatDevelopmentStatus.aspx
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Gamma-secretase 21 Target ID: CHEMBL2094135 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900185 \| https://www.ncbi.nlm.nih.gov/pubmed/23312944	Inhibitor 8297		0.3 nM [IC50]
Gamma-secretase 21 Target ID: CHEMBL2094135 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900185 \| https://www.ncbi.nlm.nih.gov/pubmed/23312944	Inhibitor 8297		0.3 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Alzheimer’s disease 272 Sources: http://adisinsight.springer.com/drugs/800028449 https://clinicaltrials.gov/ct2/show/NCT00810147	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

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

T_1/2

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: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660	healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660	Other AEs: Dizziness, Dysacusis... Other AEs: Dizziness (33.3%) Dysacusis (16.7%) Dysacusis (33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 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: https://pubmed.ncbi.nlm.nih.gov/22892585 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: https://pubmed.ncbi.nlm.nih.gov/22892585 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: https://pubmed.ncbi.nlm.nih.gov/22892585 Page: p.1434

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: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660	healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660
Dizziness	33.3%	800 mg single, oral Highest studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660	healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660
Dysacusis	33.3%	800 mg single, oral Highest studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 Page: p.660	healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22381714 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: https://pubmed.ncbi.nlm.nih.gov/22892585 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: https://pubmed.ncbi.nlm.nih.gov/22892585 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: https://pubmed.ncbi.nlm.nih.gov/22892585 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: https://pubmed.ncbi.nlm.nih.gov/22892585 Page: p.1434

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1A2 1524 CYP2C19 1478 CYPs (excluded 2C19) 1	HLM 31 P-gp 1537 UGTs 13

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006713	inconclusive [IC50 7.4266 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2012.05.519	moderate
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22420884/ \| https://pubmed.ncbi.nlm.nih.gov/18634893/	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22420884/ \| https://pubmed.ncbi.nlm.nih.gov/18634893/	no
CYPs (excluded 2C19) 1	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24900185/	no
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24900185/	weak [IC50 20 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2012.05.519	weak

Drug as victim

Target	Modality	Activity
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22420884/	likely
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22420884/	no
UGTs 13	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23713656/	no

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

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

Avagacestat (BMS-708163) inhibited gamma-secretase in human IMR32 cell membrane with IC50 0.13 nM

Substance Class	Chemical Created by `admin` on `Fri Dec 15 18:46:27 GMT 2023` Edited by `admin` on `Fri Dec 15 18:46:27 GMT 2023`
Record UNII	TQ44WWY45Q
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

AVAGACESTAT

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