Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Bioorg Med Chem Lett. 2011 Jun 1;21(11):3301-6. doi: 10.1016/j.bmcl.2011.04.028. Epub 2011 Apr 13.
A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.
通过对历史抑制剂 1 中存在的复杂 P1 基团进行修饰，发现了一种新的无手性 N-羟基甲酰胺类 ADAM-TS4 和 ADAM-TS5 的抑制剂 2。这种结构变化改善了 DMPK 性质，并大大简化了合成，同时保持了优异的跨 MMP 选择性。对 P1 基团的构效关系和构效关系的研究导致了 ADAM-TS4 选择性和混合 ADAM-TS4/5 抑制剂的产生。这导致了一种具有良好生物利用度的临床前候选药物的鉴定，预测其具有每日一次的给药动力学。
