Difluoroethylamines as an amide isostere in inhibitors of cathepsin K

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 3; pp. 920 - 923
• Main Authors: Isabel, Elise, Mellon, Christophe, Boyd, Michael J., Chauret, Nathalie, Deschênes, Denis, Desmarais, Sylvie, Falgueyret, Jean-Pierre, Gauthier, Jacques Yves, Khougaz, Karine, Lau, Cheuk K., Léger, Serge, Levorse, Dorothy A., Li, Chun Sing, Massé, Frédéric, David Percival, M., Roy, Bruno, Scheigetz, John, Thérien, Michel, Truong, Vouy Linh, Wesolowski, Gregg, Young, Robert N., Zamboni, Robert, Cameron Black, W.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-02-2011; Elsevier
• Subjects: Administration, Oral; amides; Amides - chemistry; Analytical, structural and metabolic biochemistry; Animals; bioavailability; Biological and medical sciences; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cat K; Cathepsin K; Cathepsin K - antagonists & inhibitors; Cathepsin K - metabolism; Difluoroethylamine; Dogs; Enzymes and enzyme inhibitors; Ethylamines - chemical synthesis; Ethylamines - chemistry; Ethylamines - pharmacokinetics; Fundamental and applied biological sciences. Psychology; Hydrolases; log D; Medical sciences; Miscellaneous; nitrogen; p Ka; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Rats; Difluoroethylamine; Cathepsin K; Cat K; p K a; log D; Nitrile; Intravenous administration; Rat; Sulfone; Cysteine endopeptidases; Non peptide compound; Dissociation constant; Partition coefficient; Structure activity relation; Chemical properties; pK; Dog; Fissipedia; Carnivora; Enzyme; Aminoamide; Rodentia; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Biphenyl derivatives; Animal; Hydrolases; Carboxamide; Property structure relationship; Fluorine Organic compounds; Pharmacokinetics; Lipophilicity; Physicochemical properties
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.070

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.