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Marquis, R.W. et al.

Marquis, James, Zeng, Trout, Thompson, Rahman, Yamashita, Xie, Ru, Gress, Blake, Lark, Hwang, Tomaszek, Offen, Head, Cummings, Veber,

Azepanone-based inhibitors of human cathepsin L.

The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.[1]

References

Azepanone-based inhibitors of human cathepsin L. Marquis, R.W., James, I., Zeng, J., Trout, R.E., Thompson, S., Rahman, A., Yamashita, D.S., Xie, R., Ru, Y., Gress, C.J., Blake, S., Lark, M.A., Hwang, S.M., Tomaszek, T., Offen, P., Head, M.S., Cummings, M.D., Veber, D.F. J. Med. Chem. (2005) [Pubmed]

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