Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits
Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits
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DOI：
10.1021/jm960871c
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发表时间：
1997-08-01
影响因子：
7.3
通讯作者：
Parker, DT
中科院分区：
文献类型：
--
作者：
MacPherson, LJ;Bayburt, EK;Parker, DT
利用简明的合成方法系统地确定了重组人基质分解蛋白的异羟肟酸铅抑制剂的结构-活性关系，该合成允许在模板的每个位置探索不同的功能。体外大鼠模型和体内兔关节软骨降解模型被用来进一步优化这些类似物的口服活性和作用时间。这些修饰的最终结果是CGS 27023A，一种有效的、口服活性的基质分解素抑制剂，可以阻止软骨基质的侵蚀。
Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.