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Design and synthesis of cell potent BACE-1 inhibitors: Structure–activity relationship of P1′ substituents |
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| Authors: | Jennifer M Sealy Anh P Truong Luke Tso Gary D Probst Jose Aquino Roy K Hom Barbara M Jagodzinska Darren Dressen David WG Wone Louis Brogley Varghese John Jay S Tung Michael A Pleiss John A Tucker Andrei W Konradi Michael S Dappen Gergely Toth Hu Pan Lany Ruslim Jim Miller Michael P Bova Sukanto Sinha Kevin P Quinn John-Michael Sauer |
| Institution: | 1. Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States;2. Department of Process and Analytical Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States;3. Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States;4. Department of Biology, Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States;5. Department of Lead Finding, Drug Disposition, and Safety Evaluation, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States |
| Abstract: | Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Aβ cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1′ residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux. |
| Keywords: | Alzheimer’ s disease β -Secretase (BACE-1) inhibitor Hydroxyethylamine (HEA) |
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