1. Azepanone-based inhibitors of human cathepsin L.
- Author
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Marquis RW, James I, Zeng J, Trout RE, Thompson S, Rahman A, Yamashita DS, Xie R, Ru Y, Gress CJ, Blake S, Lark MA, Hwang SM, Tomaszek T, Offen P, Head MS, Cummings MD, and Veber DF
- Subjects
- Amides chemistry, Azepines chemistry, Binding Sites, Cathepsin L, Cysteine Proteinase Inhibitors chemistry, Humans, Models, Molecular, Quinolines chemistry, Structure-Activity Relationship, Sulfones chemistry, Azepines chemical synthesis, Cathepsins antagonists & inhibitors, Cathepsins chemistry, Cysteine Endopeptidases chemistry, Cysteine Proteinase Inhibitors chemical synthesis, Sulfones chemical synthesis
- Abstract
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.
- Published
- 2005
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