Respiratory and Inflammation Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
Bioorg Med Chem Lett. 2011 Mar 1;21(5):1376-81. doi: 10.1016/j.bmcl.2011.01.036. Epub 2011 Jan 18.
Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.
从先前合成的作为基质金属蛋白酶-13（胶原酶-3）抑制剂的化合物中筛选出了两种 ADAM-TS4 的 N-羟甲酰胺抑制剂系列。使用 ADAM-TS1 作为结构替代物来了解此类化合物的结合模式，导致发现了具有良好 DMPK 性质的有效且非常选择性的抑制剂。本文描述了合成、构效关系以及提高选择性和降低体内代谢清除率的策略。
