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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Peptidic 1-cyanopyrrolidines: synthesis and SAR of a series of potent, selective cathepsin inhibitors.

1-Cyanopyrrolidines have previously been reported to inhibit cysteinyl cathepsins (Falgueyret, J.-P. et al., J. Med. Chem. 2001, 44, 94). In order to optimize binding interactions for a given cathepsin and simultaneously reduce interactions with the other closely related enzymes, small peptidic substituents were introduced to the 1-cyanopyrrolidine scaffold, either at the 2-position starting with proline or at the 3-position of aminopyrrolidines. The resulting novel compounds proved to be micromolar inhibitors of cathepsin B ( Cat B) but nanomolar to picomolar inhibitors of cathepsins K, L, and S (Cat K, Cat L, Cat S). Several of the compounds were >20-fold selective versus the other three cathepsins. SAR trends were observed, most notably the remarkable potency of Cat L inhibitors based on the 1-cyano-D-proline scaffold. The selectivity of one such compound, the 94 picomolar Cat L inhibitor 12, was demonstrated at higher concentrations in DLD-1 cells. Although none of the compounds in the proline series that was tested proved to be submicromolar in the in vitro bone resorption assay, two Cat K inhibitors in the 3-substituted pyrrolidine series, 24 and 25 were relatively potent in that assay.[1]


  1. Peptidic 1-cyanopyrrolidines: synthesis and SAR of a series of potent, selective cathepsin inhibitors. Rydzewski, R.M., Bryant, C., Oballa, R., Wesolowski, G., Rodan, S.B., Bass, K.E., Wong, D.H. Bioorg. Med. Chem. (2002) [Pubmed]
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