期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 5, 页码 1361-1365出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.01.036
关键词
Alzheimer's disease; BACE-1 inhibition; Macrocyclization; Hydroxyethylene transition-state mimetic
The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system. (C) 2009 Elsevier Ltd. All rights reserved.
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