Synthesis and evaluation of cis-hexahydropyrrolo[3,2-b]pyrrol-3-one peptidomimetic inhibitors of CAC1 cysteinyl proteinases

Fmoc-protected 5,5-bicyclic intermediates 5 and 6 were prepared through an intramolecular cyclisation of anti-epoxide 17. Building block 5 was utilised in a solid phase synthesis and building block 6 in solution syntheses of potent peptidomimetic inhibitors of a range of CAC1 cysteinyl proteinases. Compound 22 was evaluated in vitro as a low nanomolar and selective inhibitor of human cathepsin K that exhibited sub-micromolar activity in a cell-based human osteoclast assay of bone resorption.