期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 19, 期 1, 页码 145-155出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.11.042
关键词
Alzheimer's disease; BACE-1 inhibitors; tert-Hydroxyl; Transition state mimic; alpha-Phenylnorstatine; alpha-Benzylnorstatine
资金
- Swedish Research Council
- Alice and Knut Wallenberg's Foundation
- Medivir AB
Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on alpha-phenylnorstatine, alpha-benzylnorstatine, iso-serine, and beta-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 mu M) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids. (C) 2010 Elsevier Ltd. All rights reserved.
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