Triazole-linked reduced amide isosteres: an approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors |
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Authors: | Monceaux Christopher J Hirata-Fukae Chiho Lam Polo C-H Totrov Maxim M Matsuoka Yasuji Carlier Paul R |
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Institution: | a Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA b Department of Neurology, Georgetown University Medical Center, Building D, Suite 177, 4000 Reservoir Rd. NW, Washington, DC 20057, USA c Molsoft LLC, 11199 Sorrento Valley Rd., CA 92121, USA |
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Abstract: | In the course of a β-site APP-cleaving enzyme 1 (BACE1) inhibitor discovery project an in situ synthesis/screening protocol was employed to prepare 120 triazole-linked reduced amide isostere inhibitors. Among these compounds, four showed modest (single digit micromolar) BACE1 inhibition. Our ligand design was based on a potent reduced amide isostere 1, wherein the P2 amide moiety was replaced with an anti-1,2,3-triazole unit. Unfortunately, this replacement resulted in a 1000-fold decrease in potency. Docking studies of triazole-linked reduced amide isostere A3Z10 and potent oxadiazole-linked tertiary carbinamine 2a with BACE1 suggests that the docking poses of A3Z10 and 2a in the active sites are quite similar, with one exception. In the docked structures the placement of the protonated amine that engages D228 differs considerably between 2a and A3Z10. This difference could account for the lower BACE1 inhibition potency of A3Z10 and related compounds relative to 2a. |
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Keywords: | BACE1 reduced amide inhibitors Microtiter plate-based screening &lsquo Click&rsquo chemistry Diazotransfer In silico docking |
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