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Details

Stereochemistry ABSOLUTE
Molecular Formula C19H27N3O4.2H2O
Molecular Weight 397.4667
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SEMAGACESTAT DIHYDRATE

SMILES

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

InChI

InChIKey=MVWVSAKBHYNDEF-ANYPDPQESA-N
InChI=1S/C19H27N3O4.2H2O/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);2*1H2/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

Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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
Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations.
2007 Aug 24
Molecule of the month. Semagacestat.
2008 Sep
Recent developments in Alzheimer's disease therapeutics.
2009 Feb 19
Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer's disease.
2009 Jul
Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease.
2009 Jul
Gateways to clinical trials.
2009 Mar
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
Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans.
2010 Apr
ACS chemical neuroscience molecule spotlight on semagacestat (LY450139).
2010 Aug 18
Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.
2010 Dec 29
A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease.
2010 Mar 29
What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease?
2010 Nov 15
Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease.
2010 Nov 30
Inhibition of Notch signaling reduces the stem-like population of breast cancer cells and prevents mammosphere formation.
2010 Oct
REVIEW: γ-Secretase inhibitors for the treatment of Alzheimer's disease: The current state.
2010 Oct
Could lysine supplementation prevent Alzheimer's dementia? A novel hypothesis.
2010 Oct 27
Brain amyloid β protein and memory disruption in Alzheimer's disease.
2010 Sep 7
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.
2011 Nov 24
A phase 3 trial of semagacestat for treatment of Alzheimer's disease.
2013 Jul 25
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 07:48:16 UTC 2021
Edited
by admin
on Sat Jun 26 07:48:16 UTC 2021
Record UNII
66YH9K8271
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
SEMAGACESTAT DIHYDRATE
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)-, DIHYDRATE, (2S)-
Systematic Name English
LY-450139 DIHYDRATE
Code English
Classification Tree Code System Code
NCI_THESAURUS C471
Created by admin on Sat Jun 26 07:48:17 UTC 2021 , Edited by admin on Sat Jun 26 07:48:17 UTC 2021
Code System Code Type Description
PUBCHEM
9843749
Created by admin on Sat Jun 26 07:48:17 UTC 2021 , Edited by admin on Sat Jun 26 07:48:17 UTC 2021
PRIMARY
NCI_THESAURUS
C97363
Created by admin on Sat Jun 26 07:48:17 UTC 2021 , Edited by admin on Sat Jun 26 07:48:17 UTC 2021
PRIMARY
FDA UNII
66YH9K8271
Created by admin on Sat Jun 26 07:48:17 UTC 2021 , Edited by admin on Sat Jun 26 07:48:17 UTC 2021
PRIMARY
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PARENT -> SALT/SOLVATE
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ACTIVE MOIETY