Novel cathepsin K inhibitors block osteoclasts in vitro and increase spinal bone density in zebrafish.

ABSTRACT: Cathepsin K (Cat K) is a predominant cysteine protease and highly potent collagenase expressed in osteoclasts. Cat K inhibitors are anti-resorptive agents to treat osteoporosis. A novel scaffold of cathepsin K inhibitors, exemplified by lead compound 1x, was used as the template for designing and synthesizing a total of 61 derivatives that have not been reported before. An exploratory structure-activity relationship analysis identified the potent Cat K inhibitor A22, which displayed an IC₅₀ value of 0.44 μM against Cat K. A22 was very specific for Cat K and caused a significantly higher in vitro inhibition of the enzyme as compared to that of lead compound 1x. A surface plasmon resonance analysis confirmed in vitro binding of A22 to Cat K. Molecular docking studies

SUBMITTER: Xue ST 

PROVIDER: S-EPMC9061869 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature