Cathepsin D is a ubiquitous lysosomal catabolic aspartic protease. Its possible role in the pathophysiology of cancer, especially breast cancer, has been extensively studied, yet it is not fully understood. Cathepsin D also resembles many secreted proteases from human pathogens. In this study, we have developed a series of macrocyclic inhibitors composed from three subunits linked together by amide bonds, see figure below.
The first subunit (2-hydroxy-3-amino acid), contains the transition state isostere (hydroxyl group) which interacts with the active site aspartates. Its R1 substituent points towards the S1 enzyme sub-site. The second subunit (amino acid) contains R2 substituent filling the S2’ sub-site while the third one connects the other two by a chain (A) interacting with the large hydrophobic S2-S3’site of the enzyme binding cleft. Here we report synthesis and inhibitory potency of a series of inhibitors with different R1, R2 and A groups.