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

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.

Graphical abstractThe 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.Figure optionsDownload full-size imageDownload as PowerPoint slide