U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C19H27N3O4
Molecular Weight 361.4361
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SEMAGACESTAT

SMILES

CC(C)[C@@]([H])(C(=N[C@@]([H])(C)C(=N[C@@]1([H])c2ccccc2CCN(C)C1=O)O)O)O

InChI

InChIKey=PKXWXXPNHIWQHW-RCBQFDQVSA-N
InChI=1S/C19H27N3O4/c1-11(2)16(23)18(25)20-12(3)17(24)21-15-14-8-6-5-7-13(14)9-10-22(4)19(15)26/h5-8,11-12,15-16,23H,9-10H2,1-4H3,(H,20,25)(H,21,24)/t12-,15-,16-/m0/s1

HIDE SMILES / InChI

Molecular Formula C19H27N3O4
Molecular Weight 361.4361
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 3 / 3
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/22323718

Semagacestat (LY-450139) was a gamma secretase inhibitor being developed as a treatment for Alzheimer's disease by Eli Lilly. It was hoped that the drug would help to delay the onset of severe Alzheimer's disease, and thereby help preserve cognitive and executive functioning and in turn improve patient quality of life. Semagacestat (LY-450139) is designed to inhibit gamma secretase, an enzyme that is involved in the cleavage of APP to beta-amyloid. By decreasing production of beta-amyloid, it is hoped that gamma secretase inhibitors will exert a disease-modifying effect in Alzheimer's disease and thus slow or halt the destruction of nerve cells – the final stage in the amyloid cascade hypothesis. In March 2008 semagacestat (LY-450139) advanced to Phase III development, where it was evaluated in the IDENTITY (Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of AmyloId PaThologY) trial, the first Phase III trial for this new anti-dementia drug. In August 2010, Eli Lilly announced its decision to halt the development of Semagacestat. The decision was taken after analysing the preliminary results of the second Phase III clinical trial of the drug, which indicated that semagacestat failed to slow disease progression. The drug, in fact, worsened cognition and the ability to perform day-to-day activities.

Originator

Curator's Comment:: # Eli Lilly

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
38 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
PubMed

PubMed

TitleDatePubMed
Lack of specific amyloid-beta(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures.
2005 Jan
Recent developments in Alzheimer's disease therapeutics.
2009 Feb 19
Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease.
2009 Oct 22
Are γ-secretase inhibitors detrimental for Alzheimer's disease patients?
2010
ACS chemical neuroscience molecule spotlight on semagacestat (LY450139).
2010 Aug 18
A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease.
2010 Mar 29
Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease.
2010 Nov 30
Patents

Patents

Sample Use Guides

140mg administered orally, once daily for 24 months; dose reduction to 100mg or 60 mg possible due to intolerability
Route of Administration: Oral
Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability.
Substance Class Chemical
Created
by admin
on Sat Jun 26 05:45:54 UTC 2021
Edited
by admin
on Sat Jun 26 05:45:54 UTC 2021
Record UNII
3YN0602W4W
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
SEMAGACESTAT
INN   MI   USAN   WHO-DD  
USAN   INN  
Official Name English
N(SUP 2)-((2S)-2-HYDROXY-3-METHYLBUTANOYL)-N(SUP 1)-((1S)-3-METHYL-2-OXO-2,3,4,5-TETRAHYDRO-1H-3- BENZAZEPIN-1-YL)-L-ALANINAMIDE
Systematic Name English
SEMAGACESTAT [INN]
Common Name English
(2S)-2-HYDROXY-3-METHYL-N-((2S)-1-(((1S)-3-METHYL-2-OXO-2,3,4,5-TETRAHYDRO-1H-3- BENZAZEPIN-1-YL)AMINO)-1-OXOPROPAN-2-YL)BUTANAMIDE
Systematic Name English
LY450139
Code English
LY-450139
Code English
(N)-((S)-2-HYDROXY-3-METHYL-BUTYRYL)-1-(L-ALANINYL)-(S)-1-AMINO-3-METHYL-2,3,4,5- TETRAHYDRO-1H-3-BENZAZEPIN-2-ONE
Common Name English
BUTANAMIDE, 2-HYDROXY-3-METHYL-N-((1S)-1-METHYL-2-OXO-2-(((1S)-2,3,4,5-TETRAHYDRO-3-METHYL-2-OXO-1H-3-BENZAZEPIN-1-YL)AMINO)ETHYL)-, (2S)-
Systematic Name English
BUTANAMIDE, 2-HYDROXY-3-METHYL-N-((1S)-1-METHYL-2-OXO-2-(((1S)-2,3,4,5-TETRAHYDRO-3- METHYL-2-OXO-1H-3-BENZAZEPIN-1-YL)AMINO)ETHYL)-, (2S)-
Systematic Name English
SEMAGACESTAT [MI]
Common Name English
SEMAGACESTAT [WHO-DD]
Common Name English
SEMAGACESTAT [USAN]
Common Name English
Code System Code Type Description
FDA UNII
3YN0602W4W
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
CAS
425386-60-3
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
EVMPD
SUB32891
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
ChEMBL
CHEMBL520733
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
PUBCHEM
9843750
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
MERCK INDEX
M9850
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY Merck Index
DRUG BANK
DB12463
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
WIKIPEDIA
SEMAGACESTAT
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
INN
8996
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
NCI_THESAURUS
C81115
Created by admin on Sat Jun 26 05:45:54 UTC 2021 , Edited by admin on Sat Jun 26 05:45:54 UTC 2021
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
METABOLIC ENZYME -> SUBSTRATE
TARGET -> INHIBITOR
EXCRETED UNCHANGED
AMOUNT EXCRETED
URINE
METABOLIC ENZYME -> SUBSTRATE
EXCRETED UNCHANGED
FECAL
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Tmax PHARMACOKINETIC ORAL ADMINISTRATION

SINGLE DOSE

Biological Half-life PHARMACOKINETIC ORAL ADMINISTRATION

SINGLE DOSE