Bioorganic & Medicinal Chemistry Letters 2007-05-15

Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S.

Arnab K Chatterjee, Hong Liu, David C Tully, Jianhua Guo, Robert Epple, Ross Russo, Jennifer Williams, Michael Roberts, Tove Tuntland, Jonathan Chang, Perry Gordon, Thomas Hollenbeck, Christine Tumanut, Jun Li, Jennifer L Harris

Index: Bioorg. Med. Chem. Lett. 17(10) , 2899-903, (2007)

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Abstract

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.