Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 3; pp. 844 - 849
• Main Authors: Wu, Wen-Lian, Asberom, Theodros, Bara, Thomas, Bennett, Chad, Burnett, Duane A., Clader, John, Domalski, Martin, Greenlee, William J., Josien, Hubert, McBriar, Mark, Rajagopalan, Murali, Vicarel, Monica, Xu, Ruo, Hyde, Lynn A., Del Vecchio, Robert A., Cohen-Williams, Mary E., Song, Lixin, Lee, Julie, Terracina, Giuseppe, Zhang, Qi, Nomeir, Amin, Parker, Eric M., Zhang, Lili
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-02-2013
• Subjects: Alzheimer disease; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Cyclization; drugs; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Molecular Structure; proteinase inhibitors; proteinases; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Structure activity relationship; structure-activity relationships; Sulfone; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; γ-Secretase inhibitor; γ-Secretase inhibitor; Structure activity relationship; Alzheimer’s disease; Sulfone
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.047

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (−)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer’s disease. Specifically, 4-CF3 and 4-Br substituted arylsulfone analogs, (−)-1b and (−)-1c, are equipotent to compound (−)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.