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• W2171640074 abstract "!-Secretase is the enzyme responsible for the Amyloid-! plaques found in Alzheimer’s disease. Inhibition of this enzyme should prove to be very useful in combating Alzheimer’s disease by preventing this build-up. After a computational screening of the NCID-2 library a molecule was found to possess a 2propanol structure with aromatic groups on either side. This moiety was replicated by a combinatorial library of 150 compounds. These compounds were screened initially against !-secretase at 100, 50, and then 25 μM to narrow down to 17 structures showing 50% inhibition at 25 μM. The IC50 for each of the 17 molecules was found experimentally resulting in one lead compound 15, 4.93 μM ± 0.86 μM. This compound was modified by making slight changes to the 2-propanol moiety resulting in mostly loss of activity. and Glu +11. -Secretase cleaves the APP into a range of peptides from 38 to 43 residues, but the A!40 is the major product at 90% abundance. Albeit a minor product A!42, at 9% abundance, has been shown to be the more pathogenic peptide, giving the most to plaque formation (5, 3). !-Secretase was discovered in 1992 and was immediately proposed as a target for Alzheimer’s disease. It wasn’t definitively characterized until 1999 when it was identified by five different research groups using different methods. It was named differently by the different groups names included BACE (Vasser et al, 1999), !-Secretase, (Sinha et al., 1999), Asp2 (Hussain et al., 1999; Yan et al., 1999), and memapsin 2 (Lin et al., 2000) (1, 3). Although many researchers focus drug discovery towards finding the inhibitor with the lowest IC50, or binding affinity. This is only part of whether a compound can become a useable drug. The main cause of concern with a prospective drug molecule is other properties of the drug with in the patient including bioavailability and pharmicotoxic effects. !-Secretase showed to remain a good drug target not only because of the evidence between amyloid-! plaques and Alzheimer’s, but also because mice lacking the gene to produce !secretase showed no amyloid-! and initially demonstrated no adverse side effects. Although more recents studies with !-secretase knockout mice showed a decrease in the myelin sheath layers in both peripheral and central nervous cells (2). When further investigated it was found that in the early stages of development, when these sheaths first form, the concentration of !-secretase was increased when compared to that at latter stages in life. This is proposed to occur by the cleavage of Neuregulin1 by !-secretase, whose product is a growth and differentiation factor that leads to the formation of the myelin sheath. !-Secretase knockout mice were found to have the full length neuregulin1 peptide almost exclusively, while wild type mice had a mixture between it an the smaller products. This causes decreased hippocampal synaptic plasticity, decreased cognitive performance, and reduce lifespan (2). By nature !-secretase knockout mice imitates inhibition for the entire life cycle. Inhibition of !-secretase only latter in life, when Alzheimer’s disease predominantly occurs, cannot be measured this way. These side effects could only occur because of the high rate of myelination happening during development. Fluorescence Resonance Energy Transfer (FRET) One of the most difficult problems to overcome when designing a drug is being able to find the relevant biological activity of compounds 2 Honors Thesis, University of South Florida, Fall 2010, Supporting Information! J. Anderson" @default.
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• W2171640074 date "2010-01-01" @default.
• W2171640074 modified "2023-09-27" @default.
• W2171640074 title "Design, synthesis and SAR of a new class of small molecule inhibitors of β-Secretase." @default.
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