4-（苯并咪唑-2-基）-1,2,5-恶二唑-3-基胺衍生物：强效且选择性的p70S6激酶抑制剂
4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors.
作者信息
Bandarage Upul, Hare Brian, Parsons Jonathan, Pham Ly, Marhefka Craig, Bemis Guy, Tang Qing, Moody Cameron Stuver, Rodems Steve, Shah Sundeep, Adams Chris, Bravo Jose, Charonnet Emmanuelle, Savic Vladimir, Come Jon H, Green Jeremy
机构信息
Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA.
出版信息
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5191-4. doi: 10.1016/j.bmcl.2009.07.022. Epub 2009 Jul 9.
We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K(i) <1nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.
我们在此报告4-(苯并咪唑-2-基)-1,2,5-恶二唑-3-胺衍生物作为p70S6激酶抑制剂的设计与合成。对含有4-(苯并咪唑-2-基)-1,2,5-恶二唑-3-基胺骨架的筛选命中化合物进行了优化，以提高其对p70S6K的效力以及对相关激酶的选择性。利用源自蛋白激酶A（PKA）的活性位点同源模型进行基于结构的设计，从而制备出苯并咪唑5-取代化合物26和27，它们是p70S6K的高效抑制剂（抑制常数K(i)<1nM），对PKA、ROCK和糖原合成酶激酶3（GSK3）具有>100倍的选择性。
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