期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 18, 期 3, 页码 1063-1066出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.12.010
关键词
BACE-1; beta-secretase; inhibitor; acylguanidine
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S-1 and S-2' pockets leading to submicromolar BACE-1 inhibitors. (C) 2007 Elsevier Ltd. All rights reserved.
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