semagacestat   

GtoPdb Ligand ID: 6978

Synonyms: LY-450139
Compound class: Synthetic organic
Comment: Semagacestat is a small-molecule γ-secretase inhibitor that was developed by Eli Lilly as a potential treatment for Alzheimer's disease but it failed in Phase 3 clinical trials. NOTCH is also a γ-secretase substrate [3], and on-target inhibition of NOTCH receptor-related signalling by semagacestat treatment is proposed to be (at least in part) responsible for the unacceptable side effects that were noted in clinical trials, and which lead to termination of the trials [1].
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 7
Hydrogen bond donors 3
Rotatable bonds 7
Topological polar surface area 98.74
Molecular weight 361.2
XLogP 0.72
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES O=C(C(NC(=O)C(C(C)C)O)C)NC1C(=O)N(C)CCc2c1cccc2
Isomeric SMILES O=C([C@@H](NC(=O)[C@H](C(C)C)O)C)N[C@@H]1C(=O)N(C)CCc2c1cccc2
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
InChI Key PKXWXXPNHIWQHW-RCBQFDQVSA-N
References
1. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG et al.. (2013)
A phase 3 trial of semagacestat for treatment of Alzheimer's disease.
N. Engl. J. Med., 369 (4): 341-50. [PMID:23883379]
2. Kreft AF, Martone R, Porte A. (2009)
Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease.
J. Med. Chem., 52 (20): 6169-88. [PMID:19694467]
3. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA. (2000)
Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1.
Nat. Cell Biol., 2 (7): 463-5. [PMID:10878814]