MacPherson L J, Bayburt E K, Capparelli M P, Carroll B J, Goldstein R, Justice M R, Zhu L, Hu S, Melton R A, Fryer L, Goldberg R L, Doughty J R, Spirito S, Blancuzzi V, Wilson D, O'Byrne E M, Ganu V, Parker D T
Research Department, Novartis Pharmaceuticals, Summit, New Jersey 07901, USA.
J Med Chem. 1997 Aug 1;40(16):2525-32. doi: 10.1021/jm960871c.
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.
通过利用一种简洁的合成方法，系统地确定了重组人基质溶解素的一种新型异羟肟酸抑制剂的构效关系，该合成方法能够在模板的每个位置探索不同的官能团。利用基质溶解素诱导的软骨降解的大鼠离体模型和家兔体内模型，进一步优化这些类似物的口服活性和作用持续时间。这些修饰的最终成果是CGS 27023A，一种有效的、口服活性的基质溶解素抑制剂，可阻止软骨基质的侵蚀。
