Synthesis of Vinyl Sulfone-tethered Proline Derivatives as Highly Selective Cathepsin S Inhibitors

Cathepsin S (CatS), a cysteine protease belonging to the papain family, has been proposed as an attractive therapeutic target for asthma and autoimmune diseases due to the fact that CatS is closely implicated in the process of antigen presentation. Indeed, it has been reported that inhibition of CatS decreases chronic inflammatory pain in a collageninduced arthritis (CIA) model of rheumatoid arthritis. Thus, there is a growing interest among medicinal chemists to identify CatS inhibitors. Morpholineurea-leucine homophenylalanine vinyl sulfone 1 (LHVS, Figure 1) has been previously identified as a potent CatS inhibitor but limited selectivity for members of the cathepsin family. A number of selective CatS inhibitors have been reported as potential therapeutic agents, including cyanopeptide-, pyrrolopyrimidine-, aminopyrimidine-, cyanopyrazolidine-based inhibitors. Although some CatS inhibitors are currently being evaluated in clinical trials, potent and selective CatS inhibitors are still required. With respect to development of selective CatS inhibitors, we recently reported novel selective cathepsin S inhibitors based on a proline scaffold. Following up on this work, we herein report the synthesis of a series of proline analogues with vinyl sulfone group, which is a key functional group of LHVS. We evaluated these novel compounds for their in vitro CatS inhibitory activity to investigate a structure-activity relationship (SAR). The general synthetic procedure for preparing 4-sulfonyl substituted proline-derived analogues is summarized in Scheme 1. Mesylation of the commercially available proline analogue 2 was performed under Mitsunobu condition and subsequent nucleophilic substitution by a thiol afforded the thioether 4, which was converted to sulfone 5 by mCPBA oxidation. After deprotection of tert-Boc, acid chloride or