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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 W.G. 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 |
| Affiliation: | 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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