Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors
摘要:
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC(50) = 7.4 nM, the most potent ADAMTS-5 inhibitor reported so far. (c) 2009 Elsevier Ltd. All rights reserved.
环丙烷是许多临床前、临床和商业药物以及天然产物的关键特征。最丰富的合成技术是烯烃与重氮烷的金属催化反应,重氮烷是一种高能试剂,需要严格的安全预防措施。发现替代的无害试剂仍然是一个持续的挑战。在此,我们报道了未活化烯烃与活性亚甲基化合物的简单光氧化还原催化分子间环丙烷化反应。反应在中性溶剂中在空气或分子氧(O 2 )与由蓝色发光二极管光激发的光氧化还原催化剂和碘助催化剂(以分子碘形式添加或由烷基碘原位生成)。机理研究表明光敏 O 2在活性亚甲基化合物与烯烃的加成和环闭合过程中碳中心自由基的生成中起着至关重要的作用。