SEMAGACESTAT DIHYDRATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C19H27N3O4.2H2O
Molecular Weight	397.4659
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

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	H2O
Molecular Weight	18.0153
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C19H27N3O4
Molecular Weight	361.4354
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.drugdevelopment-technology.com/projects/semagacestat/
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.

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/22323718 \| https://www.ncbi.nlm.nih.gov/pubmed/19694467	Inhibitor 8297		38.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Alzheimer’s disease 272 Sources: https://clinicaltrials.gov/ct2/show/NCT01035138	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
327 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19360898	280 mg single, oral dose: 280 mg route of administration: Oral experiment type: SINGLE co-administered:	SEMAGACESTAT cerebrospinal fluid	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status:
2200 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21724950	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:	SEMAGACESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1860 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21724950	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:	SEMAGACESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
7710 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21724950	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:		SEMAGACESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
7850 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21724950	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:		SEMAGACESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Analyte	Population
3.04 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19360898	280 mg single, oral dose: 280 mg route of administration: Oral experiment type: SINGLE co-administered:	SEMAGACESTAT cerebrospinal fluid	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status:
2.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21724950	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:	SEMAGACESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21724950	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:	SEMAGACESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

Doses

Dose	Population	Adverse events
280 mg single, oral Highest studied dose Dose: 280 mg Route: oral Route: single Dose: 280 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19360898 Page: p.4	healthy, ADULT n = 5 Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19360898 Page: p.4	Sources: https://pubmed.ncbi.nlm.nih.gov/19360898 Page: p.4
100 mg 1 times / day multiple, oral Studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17, 5	unhealthy, ADULT n = 22 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17, 5	Disc. AE: Intestinal obstruction... AEs leading to discontinuation/dose reduction: Intestinal obstruction (grade 3, 4.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17, 5
140 mg 1 times / day multiple, oral Studied dose Dose: 140 mg, 1 times / day Route: oral Route: multiple Dose: 140 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17	unhealthy, ADULT n = 14 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17	Other AEs: Cardiovascular syncope... Other AEs: Cardiovascular syncope (grade 3, 7.14%) Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17
140 mg single, oral Studied dose Dose: 140 mg Route: oral Route: single Dose: 140 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21724950 Page: p.911	healthy, ADULT n = 27 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/21724950 Page: p.911	Disc. AE: neurocardiogenic syncope... AEs leading to discontinuation/dose reduction: neurocardiogenic syncope (3.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21724950 Page: p.911

AEs

AE	Significance	Dose	Population
Intestinal obstruction	grade 3, 4.5% Disc. AE	100 mg 1 times / day multiple, oral Studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17, 5	unhealthy, ADULT n = 22 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17, 5
Cardiovascular syncope	grade 3, 7.14%	140 mg 1 times / day multiple, oral Studied dose Dose: 140 mg, 1 times / day Route: oral Route: multiple Dose: 140 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17	unhealthy, ADULT n = 14 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/18695053 Page: p.17
neurocardiogenic syncope	3.7% Disc. AE	140 mg single, oral Studied dose Dose: 140 mg Route: oral Route: single Dose: 140 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21724950 Page: p.911	healthy, ADULT n = 27 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/21724950 Page: p.911

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY111454	https://www.001chemical.com/chem/search?q=DY111454
1PlusChem LLC	1P0072C4	https://www.1pchem.com/search?query=1P0072C4
A2B Chem	AD28820	http://a2bchem.com/prod/AD28820
AChemBlock	10792	http://www.achemblock.com/catalogsearch/result/?q=10792
AK Scientific	X7560	https://aksci.com/item_detail.php?cat=X7560
AOBIOUS INC	AOB3027	http://aobious.com/aobious/search?search_query=AOB3027
Angene	AGN-PC-0WAF1A	http://www.angenechemical.com/productshow/AGN-PC-0WAF1A.html
ApexBio Technology	A8190	https://www.apexbt.com/catalogsearch/result/?q=A8190
AstaTech	83046	http://astatechinc.com/CPSResult.php?CRNO=83046
BLD Pharm	BD44686	http://www.bldpharm.com/search/Search.html?keyword=BD44686
BOC Sciences	425386-60-3	http://www.bocsci.com/description.asp?cas=425386-60-3
BioSynth	J-501018	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/J-501018
Capot Chemical	20549	https://www.capotchem.com/search.do?q=20549
Cayman Chemical	16713	http://www.caymanchem.com/app/template/Product.vm/catalog/16713
Chem Scene	CS-0292	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0292
ChemShuttle	104803	https://www.chemshuttle.com/catalogsearch/result/?q=104803
Excenen	EX-A2257	http://www.excenen.com/searchresultlist.php?id=EX-A2257
Fluorochem	332533	http://www.fluorochem.co.uk/Products/Product?code=332533
Fluorochem	366686	http://www.fluorochem.co.uk/Products/Product?code=366686
Hairui	HR140870	http://www.hairuichem.com/en/product/search.do?q=HR140870
KeyOrganics	AS-42018	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-42018
Lab Network	LN01295579	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01295579
Lab Seeker	SC-98053	http://www.labseeker.com/search.php?keywords=SC-98053&category=0
LabSeeker	SC-98053	http://www.labseeker.com/search.php?keywords=SC-98053&category=0
Matrix Scientific	145203	http://www.matrixscientific.com/145203.html
MedChem Express	HY-10009	https://www.medchemexpress.com/search.html?q=HY-10009&ft=&fa=&fp=
MolPort	MolPort-009-683-180	https://www.molport.com/shop/molecule-link/MolPort-009-683-180
Molcore	MC111454	http://www.molcore.com/CatMC111454.html
Molnova	M14445	https://www.molnova.com/en/serch-list.html?keywords=M14445
MuseChem	I003524	https://www.musechem.com/product/I003524.html
Selleck Chemicals	S1594	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1594
ShangHai Biochempartner	BCP000165	http://www.biochempartner.com/search_BCP000165
Sigma Aldrich	SML1938	http://www.sigmaaldrich.com/catalog/search?term=SML1938&interface=All&N=0&mode=match%20partialmax&lang=en®ion=US&focus=product
TargetMol	T6125	https://www.targetmol.com/search?keyword=T6125
Toronto Research Chemicals	B689473	https://www.trc-canada.com/product-detail/?CatNum=B689473
Toronto Research Chemicals	S255600	https://www.trc-canada.com/product-detail/?CatNum=S255600
Wonderchem	WD064IO	http://www.wonder-chem.com/search.html?text=WD064IO
eMolecules	32278102	https://orderbb.emolecules.com/search/#?query=32278102
eNovation Chemicals	K05790	https://www.enovationchem.com/Products.asp?SEARCHTEXT=K05790&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-3747852978	https://mcule.com/MCULE-3747852978/
mcule	MCULE-4433699881	https://mcule.com/MCULE-4433699881/

PubMed

Title	Date	PubMed
Are γ-secretase inhibitors detrimental for Alzheimer's disease patients?	2010	21149978
ACS chemical neuroscience molecule spotlight on semagacestat (LY450139).	2010 Aug 18	22778845
Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.	2010 Dec 29	21190552
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.	2011 Nov 24	21995460
A phase 3 trial of semagacestat for treatment of Alzheimer's disease.	2013 Jul 25	23883379

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.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 17:30:09 GMT 2023` Edited by `admin` on `Fri Dec 15 17:30:09 GMT 2023`
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 Fri Dec 15 17:30:09 GMT 2023 , Edited by admin on Fri Dec 15 17:30:09 GMT 2023

Code System Code Type Description

PUBCHEM

9843749

Created by admin on Fri Dec 15 17:30:09 GMT 2023 , Edited by admin on Fri Dec 15 17:30:09 GMT 2023

PRIMARY

NCI_THESAURUS

C97363

Created by admin on Fri Dec 15 17:30:09 GMT 2023 , Edited by admin on Fri Dec 15 17:30:09 GMT 2023

PRIMARY

FDA UNII

66YH9K8271

Created by admin on Fri Dec 15 17:30:09 GMT 2023 , Edited by admin on Fri Dec 15 17:30:09 GMT 2023

PRIMARY

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ANHYDROUS->SOLVATE

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ACTIVE MOIETY

Details

SMILES

InChI

DescriptionSources: http://www.drugdevelopment-technology.com/projects/semagacestat/Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/22323718

CNS Activity

Originator

Approval Year

Targets

Conditions

Approved Use

Cmax

AUC

T1/2

Doses

AEs

Sourcing

PubMed

Patents

Sample Use Guides

Description
Sources: http://www.drugdevelopment-technology.com/projects/semagacestat/
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/22323718

C_max

T_1/2