The evolution of amidine-based brain penetrant BACE1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 9; pp. 2033 - 2045
• Main Authors: Oehlrich, Daniel, Prokopcova, Hana, Gijsen, Harrie J.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2014
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s; Amidines - chemistry; Amidines - pharmacokinetics; Amidines - pharmacology; Amyloid; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE; BACE1; Brain - drug effects; Brain - metabolism; Drug Discovery - methods; Humans; Inhibitor; Models, Molecular; BACE1; Amyloid; Inhibitor; Alzheimer’s; BACE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.03.025

Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer’s drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.