Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: Heterocyclic P3

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 7; pp. 1975 - 1980
• Main Authors: Tully, David C., Liu, Hong, Alper, Phil B., Chatterjee, Arnab K., Epple, Robert, Roberts, Michael J., Williams, Jennifer A., Nguyen, KhanhLinh T., Woodmansee, David H., Tumanut, Christine, Li, Jun, Spraggon, Glen, Chang, Jonathan, Tuntland, Tove, Harris, Jennifer L., Karanewsky, Donald S.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2006; Elsevier
• Subjects: Amides - chemistry; Amides - pharmacology; Animals; Biological and medical sciences; Cathepsin; Cathepsin S; Cathepsins - antagonists & inhibitors; Cathepsins - chemistry; Cathepsins - genetics; Cathepsins - physiology; Crystallography, X-Ray; Cysteine protease inhibitor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Immunomodulators; Medical sciences; Mice; Mice, Knockout; Models, Molecular; Noncovalent inhibitor; Peptidomimetics; Pharmacology. Drug treatments; Rats; Cathepsin; Cysteine protease inhibitor; Cathepsin S; Peptidomimetics; Noncovalent inhibitor; Cyclohexane derivatives; Intravenous administration; Rat; Cysteine endopeptidases; Active site; Amides; Selectivity; Structure activity relation; Chemical synthesis; Cysteine protease inhibitor: Noncovalent inhibitor; Benzoxazole derivatives; Non covalent bond; Enzyme; Aminoamide; Peptidomimetic compound; Rodentia; Oral administration; Enzyme inhibitor; Organic chlorine compounds; Immunomodulator; Peptidases; In vivo; α-Aminoacid; Vertebrata; Mammalia; Animal; Hydrolases; Indole derivatives; Pharmacokinetics; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.12.095

A series of N α-2-benzoxazolyl-α-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure–activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported. A series of N α-2-benzoxazolyl-α-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure–activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.