Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes |
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Authors: | Sandgren Veronica Agback Tatiana Johansson Per-Ola Lindberg Jimmy Kvarnström Ingemar Samuelsson Bertil Belda Oscar Dahlgren Anders |
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Affiliation: | 1. Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden;2. Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden |
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Abstract: | A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed. |
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