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Details

Stereochemistry ABSOLUTE
Molecular Formula C19H27N3O4
Molecular Weight 361.4354
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SEMAGACESTAT

SMILES

CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N[C@H]1C2=CC=CC=C2CCN(C)C1=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

Description

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.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
38.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
327 ng/mL
280 mg single, oral
SEMAGACESTAT cerebrospinal fluid
Homo sapiens
2200 ng/mL
140 mg single, oral
SEMAGACESTAT plasma
Homo sapiens
1860 ng/mL
140 mg single, oral
SEMAGACESTAT plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
7710 ng × h/mL
140 mg single, oral
SEMAGACESTAT plasma
Homo sapiens
7850 ng × h/mL
140 mg single, oral
SEMAGACESTAT plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
3.04 h
280 mg single, oral
SEMAGACESTAT cerebrospinal fluid
Homo sapiens
2.3 h
140 mg single, oral
SEMAGACESTAT plasma
Homo sapiens
2.3 h
140 mg single, oral
SEMAGACESTAT plasma
Homo sapiens

Doses

AEs

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
140mg administered orally, once daily for 24 months; dose reduction to 100mg or 60 mg possible due to intolerability
Route of Administration: Oral
In Vitro Use Guide
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.