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- W1963588056 abstract "Inhibition of gamma secretase (GS) has been the focus of multiple drug discovery efforts over the last decade. However, the successful identification of potent gamma secretase inhibitors (GSIs) also led to the discovery of unacceptable side effects associated with this mechanism, i.e., the concomitant inhibition of Notch processing by GS. The observation that some non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the production of toxic Aβ42 while sparing Aβ and Notch has prompted the development of a class of compounds commonly referred to as gamma secretase modulators (GSMs). Using solid phase extraction in combination with an ELISA assay that utilized antibodies selective for Aβ42, Aβ40, Aβ38, or total Aβ peptides, this study describes presumptive GSMs that lower Aβ42 without altering total Aβ in a HEKswe_APP cell line, rat cortical cultures, and normal mice or rats. Western blot analysis of HEK293 cells transfected with NotchΔE was used to quantify the effect of compounds on Notch processing. IC50 values for Aβ42 lowering in the HEKswe_APP cell line were between 100 nM and 50 μM . Cytotoxicity was examined and was separated from the IC50 for Aβ42 -lowering by 10-100 fold. In rat cortical cultures the compounds were 3-5 -fold less potent for Aβ42 lowering and displayed a wide range of potencies (400 nM-300 μM). The range of potencies for in vitro inhibition of Notch processing were no effect on processing at 30 uM to a large effect at 100 nM. Aβ42 lowering in vivo was explored in normal mouse and rat brain. Animals were administered a single dose of 30 mg/kg Of each compound and the effects on brain Aβ42 levels were examined in mice or rats at 3 or 4 hours, respectively. The degree of brain penetration and ability to lower Aβ42 differed for each of the compounds. Interestingly, the degree of Aβ42 lowering did not correlate with the degree of Aβ38 production. In conclusion, the pharmacodynamic effects of GSMs have been profiled and the results suggest that modulation of gamma secretase may represent a viable means of reducing Aβ42 while avoiding toxicities associated with gamma secretase inhibition." @default.
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- W1963588056 date "2009-07-01" @default.
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- W1963588056 title "P3-291: Putative gamma secretase modulators lower Aβ42 in multiple in vitro and in vivo models" @default.
- W1963588056 doi "https://doi.org/10.1016/j.jalz.2009.04.962" @default.
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