Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Québec, Canada H9H 3L1.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):887-92. doi: 10.1016/j.bmcl.2009.12.083. Epub 2009 Dec 28.
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.
MK-0674 是一种强效且选择性的组织蛋白酶 K 抑制剂，与odanacatib 同属一个结构类别，对 Cat K 的抑制作用相当。它具有口服生物利用度和在临床前物种中表现出较长的半衰期。使用氘代 MK-0674 的体内研究表明，醇手性中心通过氧化/还原循环发生立体选择性差向异构化。通过体外孵育，可以鉴定出两种代谢产物：羟基亮氨酸和葡萄糖醛酸轭合物，这两种代谢产物均使用真实的合成标准品得到了确认。
