gamma-secretase modulator 2 - CAS 1093978-89-2
Catalog number:
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
Molecular Weight:
gamma-secretase modulator 2,a triazole derivative, a potent and selective γ-secretase modulator so as to selectively attenuate production of Aβ(1-42) and hence has the potential for treatment of Alzheimer's disease.
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Brife Description:
A potent and selective γ-secretase modulator
White solid
6-fluoro-3-[4-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]triazol-1-yl]-1-(2,2,2-trifluoroethyl)-4,5-dihydro-3H-1-benzazepin-2-one; gamma-secretase modulator 2; 1093978-89-2; SCHEMBL3040102; DTXSID70732149; C25H22F4N6O2; 3374AH; ABP000472; BCP9000905; CS-0310; HE070827; HE211077; HY-50754; DB-014988; W-5511; 2H-1-BENZAZEPIN-2-ONE,6-FLUORO-1,3,4,5-TETRAHYDRO-3-[4-[3-METHOXY-4-(4-METHYL-1H-IMIDAZOL-1-YL)PHENYL]-1H-1,2,3-TRIAZOL-1-YL]-1-(2,2,2-TRIFLUOROETHYL)-; 6-fluoro-1,3,4,5-tetrahydro-3-[4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-2H-1-Benzazepin-2-on; 6-Fluoro-1,3,4,5-tetrahydro-3-[4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-2H-1-benzazepin-2-one; 6-fluoro-3-{4-[3-methoxy-4-(4-methyl-1h-imidazol-1-yl)phenyl]-1h-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2h-1-benzazepin-2-one; 6-FLUORO-3-{4-[3-METHOXY-4-(4-METHYLIMIDAZOL-1-YL)PHENYL]-1,2,3-TRIAZOL-1-YL}-1-(2,2,2-TRIFLUOROETHYL)-4,5-DIHYDRO-3H-1-BENZAZEPIN-2-ONE
Soluble to 10 mM in DMSO
Store in a cool and dry place and at 0 - 4℃ for short term (days to weeks) or -36℃ for long term (months to years).
Boiling Point:
729.8℃ at 760 mmHg
1.43 g/cm3
Canonical SMILES:
1.SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer's disease.
Flesch D1, Ness J2, Lamers C1, Dehm F3, Popella S3, Steri R1, Ogorek I2, Hieke M1, Dannhardt G4, Werz O3, Weggen S5, Schubert-Zsilavecz M6. Bioorg Med Chem Lett. 2015 Feb 15;25(4):841-6. doi: 10.1016/j.bmcl.2014.12.073. Epub 2014 Dec 30.
We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed γ-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79μM (Aβ42), 0.3μM (5-lipoxygenase) and an EC50 value of 4.64μM for PPARγ-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining γ-secretase-modulation, PPARγ-agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-modifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation.
2.Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aβ₄₂ production.
Takai T1, Koike T2, Honda E2, Kajita Y2, Nakamura M2, Morimoto S2, Hoashi Y2, Kamata M2, Watanabe T2, Igari T2, Terauchi J2. Bioorg Med Chem. 2015 May 1;23(9):1923-34. doi: 10.1016/j.bmc.2015.03.055. Epub 2015 Mar 28.
Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ₄₂ production. Lead compound 3, with selective Aβ₄₂-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aβ₄₂ in mice.
3.Single administration of a novel γ-secretase modulator ameliorates cognitive dysfunction in aged C57BL/6J mice.
Hayama T1, Murakami K1, Watanabe T1, Maeda R1, Kamata M1, Kondo S2. Brain Res. 2016 Feb 15;1633:52-61. doi: 10.1016/j.brainres.2015.12.020. Epub 2015 Dec 17.
Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early onset of Alzheimer׳s disease (AD). These proteins comprise the catalytic domain of γ-secretase, which catalyzes the cleavage of β-amyloid (Aβ) from amyloid precursor protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of presenilins by small molecules may have therapeutic potential for the treatment of cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-secretase modulator (GSM), reduced Aβ production and ameliorated cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single oral administration of compound-1 at 1 and 3mg/kg ameliorated cognitive dysfunction in aged non-transgenic mice.
4.A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP.
Weissmiller AM1, Natera-Naranjo O1, Reyna SM2, Pearn ML3, Zhao X1, Nguyen P1, Cheng S1, Goldstein LS2, Tanzi RE4, Wagner SL1, Mobley WC1, Wu C1. PLoS One. 2015 Feb 24;10(2):e0118379. doi: 10.1371/journal.pone.0118379. eCollection 2015.
Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles.
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CAS 1093978-89-2 gamma-secretase modulator 2

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