The identification of potent, selective, and bioavailable cathepsin S inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 17; pp. 4929 - 4933
• Main Authors: Gauthier, Jacques Yves, Black, W. Cameron, Courchesne, Isabelle, Cromlish, Wanda, Desmarais, Sylvie, Houle, Robert, Lamontagne, Sonia, Li, Chun Sing, Massé, Frédéric, McKay, Daniel J., Ouellet, Marc, Robichaud, Joël, Truchon, Jean-François, Truong, Vouy-Linh, Wang, Qingping, Percival, M. David
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-09-2007; Elsevier
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Antigen presentation; Biological and medical sciences; Cathepsin; Cathepsin S; Cathepsins - antagonists & inhibitors; Chemistry, Pharmaceutical - methods; Cysteine Proteinase Inhibitors - chemistry; Drug Design; Drug Evaluation, Preclinical; Enzyme inhibitors; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; Inhibitory Concentration 50; Medical sciences; Mice; Miscellaneous; Models, Chemical; Models, Molecular; Molecular Conformation; Molecular Structure; Nitrile; Pharmacology. Drug treatments; Protein Binding; Rats; Structure-Activity Relationship; Sulfone; Trifluoroethylamine; Antigen presentation; Cathepsin; Enzyme inhibitors; Nitrile; Sulfone; Trifluoroethylamine; Cathepsin S; Cyclopropane derivatives; Rat; Cysteine endopeptidases; Selectivity; Structure activity relation; Chemical synthesis; Human; Enzyme; Aminoamide; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Bioavailability; Trifluoroethyl- amine; In vitro; Peptidases; In vivo; α-Aminoacid; Vertebrata; Mammalia; Mouse; Animal; Hydrolases; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.023

The Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Qué., Canada H9H 3L1.
Highly potent, selective, and bioavailable inhibitors of human, mouse, or rat cathepsin S are described. The key structural features combine a sulfonyl moiety attached to a large group in P2 and a small substituent in P3.