Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis
Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis
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DOI：
10.1021/jm701274v
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发表时间：
2008-02-28
影响因子：
7.3
通讯作者：
Han, Hyo-Kyung
中科院分区：
文献类型：
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作者：
Li, Jie Jack;Nahra, Joe;Han, Hyo-Kyung
喹唑啉酮8和吡啶并[3，4-d]嘧啶-4-酮9作为口服活性和特异性基质金属蛋白酶-13抑制剂被发现用于治疗骨关节炎。从高通量筛选（HTS）命中噻唑并嘧啶二酮7开始，我们使用计算机辅助药物设计（CADD）和系统的构效关系（SAR）研究获得了两种化学型，8和9。它们占据独特的S1 '特异性口袋，不与Zn 2+离子结合。一些吡啶并[3，4-d]嘧啶-4-酮，如10a，具有良好的吸收、分布、代谢和消除（ADME）和安全性特征。当以极高剂量给予大鼠时，10a有效地防止骨关节炎的兔动物模型中的软骨损伤，而不诱导肌肉骨骼副作用。
Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S1'-specificity pocket and do not bind to the Zn2+ ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.