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

• Published in: Journal of medicinal chemistry Vol. 55; no. 21; pp. 9009 - 9024
• Main Authors: Weiss, Matthew M, Williamson, Toni, Babu-Khan, Safura, Bartberger, Michael D, Brown, James, Chen, Kui, Cheng, 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, Li, Vivian, Lopez, Patricia, Louie, Steven, Monenschein, Holger, Nguyen, Thomas T, Pennington, Lewis D, Rattan, Claire, San Miguel, Tisha, Sickmier, E.Allen, Wahl, Robert C, Wen, Paul H, Wood, Stephen, Xue, Qiufen, Yang, Bryant H, Patel, Vinod F, Zhong, Wenge
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-11-2012
• Subjects: Administration, Oral; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological Availability; Brain - drug effects; Brain - metabolism; Crystallography, X-Ray; Dioxolanes - chemical synthesis; Dioxolanes - pharmacokinetics; Dioxolanes - pharmacology; Dogs; Drug Design; Ethylamines - chemical synthesis; Ethylamines - pharmacokinetics; Ethylamines - pharmacology; Humans; Macaca mulatta; Male; Microsomes, Liver - metabolism; Models, Molecular; Peptide Fragments - metabolism; Protein Conformation; Protein Transport; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300119p

A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-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 β-amyloid (Aβ) in Sprague–Dawley rats following oral administration.