Semagacestat - CAS 425386-60-3
Catalog number: 425386-60-3
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C19H27N3O4
Molecular Weight:
361.44
COA:
Inquire
Targets:
γ-secretase
Description:
Semagacestat is an inhibitor of the γ-secretase complex that blocks the production of Aβ38 (IC50= 12.0 nM), Aβ40 (IC50= 12.1 nM), and Aβ42 (IC50= 10.9 nM) from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium. In vitro: blocks the production of Aβ38 (IC50= 12.0 nM), Aβ40 (IC50= 12.1 nM), and Aβ42 (IC50= 10.9 nM) without affecting cell viability. In vivo: decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases β-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test.
Brife Description:
A potent inhibitor of γ-secretase; Blocks Notch signaling (IC50 = 14.1 nM)
Appearance:
White to off-white solid
Synonyms:
(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide; LY 411,575; LY 411575; LY 450139; LY-411,575; LY-411575; LY411,575; LY411575; LY450139; N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; N2-(2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)alaninamide; Semagacestat; 425386-60-3
Solubility:
Soluble to 70mg/mL in DMSO, to 41mg/mL in Ethanol
Storage:
Store in a cool and dry place and at 0 - 4℃ for short term (days to weeks) or -45℃ for long term (months to years).
MSDS:
Inquire
Boiling Point:
681.904℃ at 760 mmHg
Density:
1.221 g/cm3
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
Canonical SMILES:
CC(C)C(C(=O)NC(C)C(=O)NC1C2=CC=CC=C2CCN(C1=O)C)O
1.Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β of Peptides in Cerebrospinal Fluid Specimens from Alzheimer’s Disease Studies.
Lachno DR1, Evert BA, Maloney K, Willis BA, Talbot JA, Vandijck M, Dean RA. J Alzheimers Dis. 2015;45(2):527-42.
The aim of this study was to validate assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF)specimens according to regulatory guidance and demonstrate their utility with measurements in specimens from Alzheimer’s disease (AD) studies. Methods based on INNOTEST(®)β-AMYLOID(1-42) and prototype INNOTEST(®)β-AMYLOID(1-40) ELISAkits were developed involving pre-analytical sample treatment with Tween-20 for reliable analyte recovery.Validation parameters were evaluated by repeated testing of CSF pools collected and stored in the same manner as clinical specimens. Intra- and interassay coefficients of variation were ≤11% and relative accuracy was within ± 10% for both analytes. Dilutional linearity was demonstrated for both analytes from a spiked CSF pool, but not from a non-spiked native CSF pool. Recovery of standard Aβ peptide spikes standard ranged from 77% to 93%. No interference was observed from the investigational drugs LY2811376, LY2886721, LY3002813, or semagacestat.
2.A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS).
Wessels AM1, Siemers ER1, Yu P1, Andersen SW1, Holdridge KC1, Sims JR1, Sundell K1, Stern Y2, Rentz DM3, Dubois B4, Jones RW5, Cummings J6, Aisen PS7. J Prev Alzheimers Dis. 2015 Dec 1;2(4):227-241.
It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences.
3.Lessons from a failed γ-secretase Alzheimer trial.
De Strooper B1. Cell. 2014 Nov 6;159(4):721-6. doi: 10.1016/j.cell.2014.10.016.
γ-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum γ-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing γ-secretase research therapeutically. This pessimism is unwarranted: analysis of available information presented here demonstrates significant confounds for interpreting the outcome of the trial and argues that the major lessons pertain to broad knowledge gaps that are imperative to fill.
4.What lessons can be learned from failed Alzheimer's disease trials?
Toyn J1. Expert Rev Clin Pharmacol. 2015 May;8(3):267-9. doi: 10.1586/17512433.2015.1034690. Epub 2015 Apr 10.
Trials missing primary efficacy end points raise the question of whether the choice of drug or the limitations of disease biology were at fault. In some trials, drugs appear not to have achieved biochemical effect thresholds sufficient for clinical benefit. This suggests the need for improved drugs that are more active at tolerated doses. In other trials, it is unclear how the observed biomarker changes are related to potential efficacy. However, hints of efficacy from exploratory analyses support the idea that starting treatment earlier in the course of the disease might be more effective. A closer look at the failed trials will help de-risk future trials.
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CAS 425386-60-3 Semagacestat

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