1. Difluoroethylamines as an amide isostere in inhibitors of cathepsin K
- Author
-
Elise Isabel, Christophe Mellon, Michael J. Boyd, Nathalie Chauret, Denis Deschênes, Sylvie Desmarais, Jean-Pierre Falgueyret, Jacques Yves Gauthier, Karine Khougaz, Cheuk K. Lau, Serge Léger, Dorothy A. Levorse, Chun Sing Li, Frédéric Massé, M. David Percival, Bruno Roy, John Scheigetz, Michel Thérien, Vouy Linh Truong, Gregg Wesolowski, Robert N. Young, Robert Zamboni, and W. Cameron Black
- Subjects
Stereochemistry ,Clinical Biochemistry ,Cathepsin K ,Pharmaceutical Science ,Administration, Oral ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Dogs ,Amide ,Drug Discovery ,Ethylamines ,Animals ,Protease Inhibitors ,Molecular Biology ,Cathepsin ,biology ,Organic Chemistry ,Biphenyl Compounds ,Active site ,Amides ,Rats ,Biphenyl compound ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Odanacatib - Abstract
The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
- Published
- 2010