Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 19; pp. 5112 - 5117
• Main Authors: Tully, David C., Liu, Hong, Chatterjee, Arnab K., Alper, Phil B., Epple, Robert, Williams, Jennifer A., Roberts, Michael J., Woodmansee, David H., Masick, Brian T., Tumanut, Christine, Li, Jun, Spraggon, Glen, Hornsby, Michael, Chang, Jonathan, Tuntland, Tove, Hollenbeck, Thomas, Gordon, Perry, Harris, Jennifer L., Karanewsky, Donald S.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.10.2006; Elsevier
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - pharmacokinetics; Amides - pharmacology; Animals; Binding Sites; Biological and medical sciences; Biological Availability; Cathepsin S; Cathepsins - antagonists & inhibitors; Crystallography, X-Ray; Cysteine protease inhibitor; Ethers, Cyclic - chemical synthesis; Ethers, Cyclic - pharmacology; Humans; Male; Medical sciences; Miscellaneous; Molecular Structure; Noncovalent inhibitor; Peptidomimetic; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Rats; Rats, Wistar; Structure-Activity Relationship; X-ray structure; Zinc; Cysteine protease inhibitor; Cathepsin S; Peptidomimetic; X-ray structure; Noncovalent inhibitor; Cyclohexane derivatives; Intravenous administration; Rat; Cysteine endopeptidases; Active site; Furan derivatives; Amides; Morpholine derivatives; Optimization; Structure activity relation; Chemical synthesis; Non covalent bond; Enzyme; Peptidomimetic compound; Rodentia; Oral administration; Enzyme inhibitor; Aniline derivatives; Inhibitor enzyme complex; Bioavailability; In vitro; Peptidases; Vertebrata; Mammalia; Animal; Hydrolases; Pharmacokinetics; Physicochemical properties; Aromatic amine; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.07.033

The synthesis and SAR a series of arylaminoethyl amide cathepsin S inhibitors are reported, focusing on the optimization of P3 and P2 subunits. An X-ray co-crystal structure of compound 37 bound to the active site of cathepsin S is also disclosed. The synthesis and structure–activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.