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J Med Chem. 2003 May 8;46(10):1799-802.

Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human beta-secretase.

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1
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA.

Abstract

We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.

PMID:
12723942
DOI:
10.1021/jm025619l
[Indexed for MEDLINE]
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