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Azepanone-based inhibitors of human cathepsin S: optimization of selectivity via the P2 substituent.

Bioorganic & medicinal chemistry letters (2011-07-08)
Jeffrey K Kerns, Hong Nie, William Bondinell, Katherine L Widdowson, Dennis S Yamashita, Attiq Rahman, Patricia L Podolin, Donald C Carpenter, Qi Jin, Benoit Riflade, Xiaoyang Dong, Neysa Nevins, Paul M Keller, Laura Mitchell, Thaddeus Tomaszek
RÉSUMÉ

A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent. The cellular potency of selected analogs is also described.

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Cathepsin S Active human, recombinant, expressed in FreeStyle 293-F cells, ≥90% (SDS-PAGE)