Inhibition of cathepsin D by substrate analogs containing statine and by analogs of pepstatin

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Abstract
Five new cathepsin D inhibitors were synthesized and tested as inhibitors of bovine cathepsin D. The compounds were derived by replacing a Phe-Phe dipeptidyl unit of a good cathepsin D substrate, Boc-Phe-Leu-Ala-Phe-Phe-Val-Leu-OR, with statine ((3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta) or with Sta-Phe. The best inhibitor, Boc-Phe-Leu-Ala-(S,S)-Sta-Val-Leu-OMe, inhibited cathepsin D with a Ki value of 1.1 nM. In general, the more effective inhibitors were consistent with the proposal that statine functions as a replacement for a dipeptidyl unit. Thirty-five known pepstatin analogues also were evaluated as cathepsin D inhibitors. Substituents in the P4 and P3'' positions are important for maximal inhibition of this aspartic proteinase, and the P4 substituent appears more important for inhibition of cathepsin D than for inhibition of other aspartic proteinases.