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Bioorg Med Chem Lett. 2007 May 15;17(10):2899-903. Epub 2007 Feb 27.

Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S.

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Genomics Institute of the Novartis Research Foundation (GNF), 10675 John J. Hopkins Dr., San Diego, CA 92121, USA.


Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues.

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