Semagacestat

Semagacestat

Clinical data
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	Development terminated
Pharmacokinetic data
Metabolism	CYP3A4, 3A5
Biological half-life	2.4 hours in circulation
Excretion	87% renal (44% unchanged, 43% as metabolites)
Identifiers
IUPAC name (2S)-2-Hydroxy-3-methyl-N-((1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide
Synonyms	LY-450139
CAS Number	425386-60-3 Y
PubChem CID	9843750
IUPHAR/BPS	6978
ChemSpider	8019465 N
UNII	3YN0602W4W
KEGG	D09377 Y
ChEMBL	CHEMBL520733 N
Chemical and physical data
Formula	C19H27N3O4
Molar mass	361.434 g/mol
3D model (Jmol)	Interactive image
SMILES C[C@@H](C(=O)N[C@H]1C2=CC=CC=C2CCN(C1=O)C)NC(=O)[C@H](C(C)C)O
InChI 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 N Key:PKXWXXPNHIWQHW-RCBQFDQVSA-N N
NY (what is this?)

Semagacestat (LY-450139) was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Élan, and clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped.

β-Amyloid is a peptide of 39 to 43 amino acids. The isoforms with 40 and 42 amino acids (Aβ40/42) are the main constituents of amyloid plaques in the brains of Alzheimer's disease patients. β-Amyloid is formed by proteolysis of amyloid precursor protein (APP). Research on laboratory rats suggest that the soluble form of this peptide is a causative agent in the development of Alzheimer's.

Semagacestat blocks the enzyme γ-secretase, which (along with β-secretase) is responsible for APP proteolysis.

Phase III double-blind clinical trials started in March 2008 with the IDENTITY study (Interrupting Alzheimer's dementia by evaluating treatment of amyloid pathology), including 1500 patients from 22 countries. This study was intended to run until May 2011. The successor trial with further 1500 patients, IDENTITY-2, started in September 2008. The open-label trial IDENTITY-XT, which included patients who have completed one of the two studies, started in December 2009. On 17 August 2010, it was announced that the phase III trials failed. Preliminary findings show that not only did semagacestat fail to slow disease progression, but that it was actually associated with “worsening of clinical measures of cognition and the ability to perform activities of daily living”. Furthermore, the incidence of skin cancer was significantly higher in the treatment group than the placebo group.

A number of issues have already been raised during clinical trials: