Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: Winneroski, Leonard L.; Erickson, Jon A.; Green, Steven J.; Lopez, Jose E.; Stout, Stephanie L.; Porter, Warren J.; Timm, David E.; Audia, James E.; Barberis, Mario; Beck, James P.; Boggs, Leonard N.; Borders, Anthony R.; Boyer, Robert D.; Brier, Richard A.; Hembre, Erik J.; Hendle, Jörg; Garcia-Losada, Pablo; Minguez, Jose Miguel; Mathes, Brian M.; May, Patrick C.; Monk, Scott A.; Rankovic, Zoran; Shi, Yuan; Watson, Brian M.; Yang, Zhixiang; Mergott, Dustin J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 1(2020)
• Publication Date: 2020-01-01
• Subjects: BACE1 inhibitor -- Alzheimer's disease -- Cyclopropyl -- Conformational constraint -- Structure-based drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115194
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans -cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.