Gilbert Adam M, Bursavich Matthew G, Lombardi Sabrina, Georgiadis Katy E, Reifenberg Erica, Flannery Carl R, Morris Elisabeth A
Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
Bioorg Med Chem Lett. 2007 Mar 1;17(5):1189-92. doi: 10.1016/j.bmcl.2006.12.020. Epub 2006 Dec 12.
A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).
本文描述了一系列5-((1H-吡唑-4-基)亚甲基)-2-硫代噻唑烷-4-酮类ADAMTS-5（软骨聚集蛋白聚糖酶-2）抑制剂。这些化合物对ADAMTS-5具有微摩尔级的功能抑制作用，代表了一类新型药物，具有抑制聚集蛋白聚糖降解的潜力，聚集蛋白聚糖是软骨的主要成分，在骨质疏松症中会流失。化合物12值得注意，其ADAMTS-5的IC50为1.1微摩尔，对ADAMTS-4（软骨聚集蛋白聚糖酶-1）的功能选择性大于40倍。
