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通过有利的P1'、P1和/或P3取代，具有良好药代动力学性质的组织蛋白酶K的强效和选择性P2 - P3酮酰胺抑制剂。

Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions.

作者信息

Barrett David G, Catalano John G, Deaton David N, Hassell Anne M, Long Stacey T, Miller Aaron B, Miller Larry R, Shewchuk Lisa M, Wells-Knecht Kevin J, Willard Derril H, Wright Lois L

机构信息

Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.

出版信息

Bioorg Med Chem Lett. 2004 Oct 4;14(19):4897-902. doi: 10.1016/j.bmcl.2004.07.031.

DOI:10.1016/j.bmcl.2004.07.031
PMID:15341947
Abstract

A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.

摘要

合成了一系列酮酰胺，并对其针对组织蛋白酶K的抑制活性进行了评估。基于分子模型建议，探索了非手性P(2)取代基与半胱氨酸蛋白酶之间的相互作用，得到了对组织蛋白酶K具有强效抑制活性的化合物，这些化合物对组织蛋白酶B、H和L表现出高选择性。随后对P(3)、P(1)和P(1')部分进行修饰，得到了口服生物可利用的抑制剂。

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