Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 1; pp. 115194 - 115200
• Main 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.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2020; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE1 inhibitor; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Conformational constraint; Crystallography, X-Ray; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Cyclopropyl; Dose-Response Relationship, Drug; Humans; Life Sciences & Biomedicine; Ligands; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Physical Sciences; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Structure-based drug design; Cyclopropyl; BACE1 inhibitor; Conformational constraint; Structure-based drug design; Alzheimer’s disease; BETA-SECRETASE; AMYLOID-BETA; MICE; Alzheimer's disease
• DOI: 10.1016/j.bmc.2019.115194
• ISSN: 0968-0896; 1464-3391

[Display omitted] 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.