ArrayBioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5533-7. doi: 10.1016/j.bmcl.2011.06.097. Epub 2011 Jul 2.
Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.
报告了一系列新型 B-Raf(V600E)抑制剂的构效关系。比较了两个相关铰链结合基团衍生的抑制剂的酶和细胞效力，结果表明 3-甲氧基吡唑并吡啶具有更好的效果。先导 B-Raf(V600E)抑制剂 1 的 3-烷氧基被延长，对效力的影响最小。化合物 1 的丙基磺酰胺尾部占据了由αC-螺旋向外移动形成的小疏脂口袋，被扩展为一系列芳基磺酰胺。X 射线晶体学揭示了这个疏脂口袋出人意料地扩大，以容纳更大的芳基基团。
