Potent benzoazepinone γ-secretase modulators with improved bioavailability

Autor:	Hugh Nuthall, Lily Y. Moy, Candia M. Kenific, Sean P. Ahearn, Damaris Diaz, Elizabeth Helen Kelley, Bethany Hughes, Armetta D. Hill, Adam J. Schell, Nadya Smotrov, Valentina V. Jeliazkova-Mecheva, Chris Moxham, Hua Zhou, Sanjiv J. Shah, Andrew Rosenau, Alexey Rivkin, Sam Kattar, Joey L. Methot, Richard G. Ball, William Brown, Mark S. Shearman, Chaomin Li, Christian Fischer, Alexander A. Szewczak, Sujal V. Deshmukh, Dawn M. Mampreian, Thomas A. Miller, Benito Munoz
Rok vydání:	2015
Předmět:	Genetically modified mouse Clinical Biochemistry hERG Biological Availability Pharmaceutical Science Mice Transgenic Pharmacology Biochemistry Mice chemistry.chemical_compound Pharmacokinetics Alzheimer Disease Amide Drug Discovery medicine Animals Moiety Molecular Biology biology Chemistry Organic Chemistry medicine.disease Rats Bioavailability biology.protein Molecular Medicine Amyloid Precursor Protein Secretases Alzheimer's disease Amyloid precursor protein secretase
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 25:3495-3500
ISSN:	0960-894X
Popis:	The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7a00409b5294ccf9d203089fa0df9362 https://doi.org/10.1016/j.bmcl.2015.06.032 Zobrazit plný text záznamu Full Text from ScienceDirect