Acylguanidines as Small-Molecule -Secretase Inhibitors
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- 作者：Derek C. Cole ; Eric S. Manas ; Joseph R. Stock ; Jeffrey S. Condon ; Lee D. Jennings ; Ann Aulabaugh ; Rajiv Chopra ; Rebecca Cowling ; John W. Ellingboe ; Kristi Y. Fan ; Boyd L. Harrison ; Yun Hu ; Steve Jacob
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 19, 2006
- 年：2006
- 卷：49
- 期：21
- 页码：6158 - 6161
- 全文大小：244K
- 年卷期：v.49,no.21(October 19, 2006)
- ISSN：1520-4804
文摘
BACE1 is an aspartyl protease responsible for cleavingamyloid precursor protein to liberate A
, which aggregates leading toplaque deposits implicated in Alzheimer's disease. We have identifiedsmall-molecule acylguanidine inhibitors of BACE1. Crystallographicstudies show that these compounds form unique hydrogen-bondinginteractions with the catalytic site aspartic acids and stabilize the proteinin a flap-open conformation. Structure-based optimization led to theidentification of potent analogs, such as 10d (BACE1 IC50 = 110 nM).
, which aggregates leading toplaque deposits implicated in Alzheimer's disease. We have identifiedsmall-molecule acylguanidine inhibitors of BACE1. Crystallographicstudies show that these compounds form unique hydrogen-bondinginteractions with the catalytic site aspartic acids and stabilize the proteinin a flap-open conformation. Structure-based optimization led to theidentification of potent analogs, such as 10d (BACE1 IC50 = 110 nM).