1404070-33-2Relevant academic research and scientific papers
Synthesis of a potent photoreactive acidic γ-secretase modulator for target identification in cells
Rennhack, Andreas,Bulic, Bruno,Jumpertz, Thorsten,Ness, Julia,Baches, Sandra,Weggen, Sascha,Pietrzik, Claus U.
supporting information, p. 6523 - 6532,10 (2012/12/12)
Supramolecular self-assembly of amyloidogenic peptides is closely associated with numerous pathological conditions. For instance, Alzheimers disease (AD) is characterized by abundant amyloid plaques originating from the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Compounds named γ-secretase modulators (GSMs) can shift the substrate cleavage specificity of γ-secretase toward the production of non-amyloidogenic, shorter Aβ fragments. Herein, we describe the synthesis of highly potent acidic GSMs, equipped with a photoreactive diazirine moiety for photoaffinity labeling. The probes labeled the N-terminal fragment of presenilin (the catalytic subunit of γ-secretase), supporting a mode of action involving binding to γ-secretase. This fundamental step toward the elucidation of the molecular mechanism governing the GSM-induced shift in γ-secretase proteolytic specificity should pave the way for the development of improved drugs against AD.
Synthesis of a potent photoreactive acidic γ-secretase modulator for target identification in cells
Rennhack, Andreas,Jumpertz, Thorsten,Ness, Julia,Baches, Sandra,Pietrzik, Claus U.,Weggen, Sascha,Bulic, Bruno
supporting information, p. 6523 - 6532 (2013/01/14)
Supramolecular self-assembly of amyloidogenic peptides is closely associated with numerous pathological conditions. For instance, Alzheime?s disease (AD) is characterized by abundant amyloid plaques originating from the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Compounds named γ-secretase modulators (GSMs) can shift the substrate cleavage specificity of γ-secretase toward the production of non-amyloidogenic, shorter Aβ fragments. Herein, we describe the synthesis of highly potent acidic GSMs, equipped with a photoreactive diazirine moiety for photoaffinity labeling. The probes labeled the N-terminal fragment of presenilin (the catalytic subunit of γ-secretase), supporting a mode of action involving binding to γ-secretase. This fundamental step toward the elucidation of the molecular mechanism governing the GSM-induced shift in γ-secretase proteolytic specificity should pave the way for the development of improved drugs against AD.
Fluorinated piperidine acetic acids as γ-secretase modulators
Stanton, Matthew G.,Hubbs, Jed,Sloman, David,Hamblett, Christopher,Andrade, Paula,Angagaw, Minilik,Bi, Grace,Black, Regina M.,Crispino, Jamie,Cruz, Jonathan C.,Fan, Eric,Farris, Georgia,Hughes, Bethany L.,Kenific, Candia M.,Middleton, Richard E.,Nikov, George,Sajonz, Peter,Shah, Sanjiv,Shomer, Nirah,Szewczak, Alexander A.,Tanga, Flobert,Tudge, Matthew T.,Shearman, Mark,Munoz, Benito
scheme or table, p. 755 - 758 (2010/05/19)
We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor. Compounds 1f and 2c were selec
