Design and Preparation of a Potent Series of Hydroxyethylamine Containing beta-Secretase Inhibitors That Demonstrate Robust Reduction of Central beta-Amyloid

作者：Weiss Matthew M^*; Williamson Toni; Babu Khan Safura; Bartberger Michael D; Brown James; Chen Kui; Chen Yuan; Citron Martin; Croghan Michael D; Dineen Thomas A; Esmay Joel; Graceffa Russell F; Harried Scott S; Hickman Dean; Hitchcock Stephen A; Horne Daniel B; Huang Hongbing; Imbeah Ampiah Ronke; Judd Ted; Kaller Matthew R; Kreiman Charles R; La Daniel S; Lopez Patricia; Louie Steven; Monenschein Holger; Nguyen Thomas T; Pennington Lewis D; Rattan Claire

来源：Journal of Medicinal Chemistry, 2012, 55(21): 9009-9024.

DOI：10.1021/jm300119p

A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.

• 出版日期2012-11-8