1. Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints
- Author
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David E. Timm, Leonard N. Boggs, Brian Michael Mathes, Yuan Shi, Mario Barberis, Zhixiang Yang, Dustin J. Mergott, Scott A. Monk, Pablo Garcia-Losada, Jose Miguel Minguez, Leonard L. Winneroski, Jon A. Erickson, Richard A. Brier, Anthony R. Borders, Stephanie L. Stout, Porter Warren J, Zoran Rankovic, Jose Eduardo Lopez, Erik James Hembre, James E. Audia, Jorg Hendle, James P. Beck, Steven James Green, Brian Morgan Watson, Patrick C. May, and Robert D. Boyer
- Subjects
Cyclopropanes ,Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alzheimer Disease ,mental disorders ,Drug Discovery ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,Molecular Biology ,Biological evaluation ,Hydrolase inhibitor ,Dose-Response Relationship, Drug ,Chemistry ,Organic Chemistry ,Biological activity ,Ligand (biochemistry) ,Molecular Medicine ,Organic synthesis ,Amyloid Precursor Protein Secretases - 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.
- Published
- 2020