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Bioorg Med Chem Lett. 2007 Mar 15;17(6):1788-92. Epub 2006 Dec 21.

Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation.

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1
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shaun_stauffer@merck.com

Abstract

A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.

PMID:
17257835
DOI:
10.1016/j.bmcl.2006.12.051
[Indexed for MEDLINE]
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