P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K
P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K
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DOI：
10.1016/j.bmcl.2005.05.062
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发表时间：
2005-08-01
影响因子：
2.7
通讯作者：
Zhou, HQQ
中科院分区：
文献类型：
--
作者：
Barrett, DG;Boncek, VM;Zhou, HQQ
一系列口服生物可利用的酮酰胺基组织蛋白酶 K 抑制剂已被鉴定出，具有良好的药代动力学特性。从药物特性较差的强效抑制剂开始，p(2)-p(3) 连接体的构象限制和 P-1' 元件的修饰导致效力、溶解度、清除率和生物利用度的增强。这些优化的抑制剂减弱了大鼠 TPTX 低钙血症骨吸收模型中的骨吸收。 (c) 2005 Elsevier Ltd. 保留所有权利。
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the p(2)-p(3) linker and modifications to P-1' elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model. (c) 2005 Elsevier Ltd. All rights reserved.