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J Med Chem. 2006 Oct 19;49(21):6158-61.

Acylguanidines as small-molecule beta-secretase inhibitors.

Author information

1
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. coledc@wyeth.com

Abstract

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).

PMID:
17034121
DOI:
10.1021/jm0607451
[Indexed for MEDLINE]

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