期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 2, 页码 603-607出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.11.092
关键词
Alzheimer's disease; BACE-1 inhibitors; MDR1-MDCK; P-Glycoprotein; Reduction of Abeta in transgenic APP51/16 mice
A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Ab in human APP-wildtype transgenic (APP51/16) mice after oral administration. (C) 2009 Elsevier Ltd. All rights reserved.
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