| Autor: |
Marquis RW; Department of Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Robert.W.Marquis@gsk.com, 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, Veber DF |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2005 Nov 03; Vol. 48 (22), pp. 6870-8. |
| DOI: |
10.1021/jm0502079 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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