gamma-secretase modulator 3 - CAS 1431697-84-5
Catalog number:
1431697-84-5
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C24H23FN4OS
Molecular Weight:
434.53
COA:
Inquire
Targets:
γ-secretase
Description:
gamma-secretase modulator 3 is a γ-secretase inhibitor.
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Brife Description:
A γ-secretase modulator
Appearance:
White solid
Synonyms:
4-(4-fluorophenyl)-N-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine; gamma-secretase modulator 3; CS-1149; HY-50889; W-6019; 1431697-84-5
Solubility:
Soluble to 10 mM in DMSO
Storage:
Store in a cool and dry place and at 0 - 4℃ for short term (days to weeks) or -37℃ for long term (months to years).
MSDS:
Inquire
Boiling Point:
615.5±65.0℃ at 760 Torr
Density:
1.34±0.1 g/cm3 (Calc.)
InChIKey:
UCGDOBMXNQTSSO-UHFFFAOYSA-N
InChI:
1S/C24H23FN4OS/c1-15-13-29(14-26-15)20-11-10-18(12-21(20)30-2)27-24-28-23-19(4-3-5-22(23)31-24)16-6-8-17(25)9-7-16/h6-14,19H,3-5H2,1-2H3,(H,27,28)
Canonical SMILES:
CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(S3)CCCC4C5=CC=C(C=C5)F)OC
1.Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers.
Liu Q1, Waltz S1, Woodruff G2, Ouyang J3, Israel MA4, Herrera C2, Sarsoza F1, Tanzi RE5, Koo EH1, Ringman JM6, Goldstein LS2, Wagner SL1, Yuan SH1. JAMA Neurol. 2014 Dec;71(12):1481-9. doi: 10.1001/jamaneurol.2014.2482.
IMPORTANCE: Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells.
2.Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase.
Kanatsu K1, Morohashi Y2, Suzuki M3, Kuroda H4, Watanabe T3, Tomita T5, Iwatsubo T6. Nat Commun. 2014 Feb 28;5:3386. doi: 10.1038/ncomms4386.
A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (PICALM/CALM) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.
3.Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.
Jung JI1,2,3, Price AR4,5,6, Ladd TB7,8,9, Ran Y10,11,12, Park HJ13,14,15, Ceballos-Diaz C16,17,18, Smithson LA19,20,21, Hochhaus G22, Tang Y23, Akula R24, Ba S24, Koo EH25,26, Shapiro G27, Felsenstein KM28,29,30, Golde TE31,32,33. Mol Neurodegener. 2015 Jul 14;10:29. doi: 10.1186/s13024-015-0021-z.
BACKGROUND: Amyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM.
4.γ-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of β-carboxyl-terminal fragment.
Matsumura N1, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, Tagami S, Funamoto S, Ihara Y, Morishima-Kawashima M. J Biol Chem. 2014 Feb 21;289(8):5109-21. doi: 10.1074/jbc.M113.510131. Epub 2013 Dec 28.
γ-Secretase generates amyloid β-protein (Aβ), a pathogenic molecule in Alzheimer disease, through the intramembrane cleavage of the β-carboxyl-terminal fragment (βCTF) of β-amyloid precursor protein. We previously showed the framework of the γ-secretase cleavage, i.e. the stepwise successive processing of βCTF at every three (or four) amino acids. However, the membrane integrity of γ-secretase was not taken into consideration because of the use of the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid-solubilized reconstituted γ-secretase system. Here, we sought to address how the membrane-integrated γ-secretase cleaves βCTF by using γ-secretase associated with lipid rafts. Quantitative analyses using liquid chromatography-tandem mass spectrometry of the βCTF transmembrane domain-derived peptides released along with Aβ generation revealed that the raft-associated γ-secretase cleaves βCTF in a stepwise sequential manner, but novel penta- and hexapeptides as well as tri- and tetrapeptides are released.
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CAS 1431697-84-5 gamma-secretase modulator 3

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