Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
J Med Chem. 2017 Jul 13;60(13):5933-5939. doi: 10.1021/acs.jmedchem.7b00650. Epub 2017 Jun 29.
Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC is 5 mg q.d.
聚集蛋白聚糖酶-1 和 -2（ADAMTS-4 和 ADAMTS-5）是参与软骨中聚集蛋白聚糖降解的锌金属蛋白酶。抑制剂可能提供一种改变骨关节炎进展的方法。我们报告了 7 种抑制剂的鉴定，它们在大鼠中具有良好的口服药代动力学特性，并在大鼠骨关节炎化学模型中显示出疗效。为了达到持续的血浆水平≥人 ADAMTS-5 IC 的 10 倍，预计人类所需的剂量为每天 5 毫克。
