Optimization of Diarylthiazole B-Raf Inhibitors: Identification of a Compound Endowed with High Oral Antitumor Activity, Mitigated hERG Inhibition, and Low Paradoxical Effect
作者:Maurizio Pulici、Gabriella Traquandi、Chiara Marchionni、Michele Modugno、Rosita Lupi、Nadia Amboldi、Elena Casale、Nicoletta Colombo、Luca Corti、Marina Fasolini、Fabio Gasparri、Wilma Pastori、Alessandra Scolaro、Daniele Donati、Eduard Felder、Arturo Galvani、Antonella Isacchi、Enrico Pesenti、Marina Ciomei
DOI:10.1002/cmdc.201402424
日期:2015.2
oncogenesis. As part of a project aimed at finding inhibitors of B‐Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration
在人类癌症中经常观察到有丝分裂原激活的蛋白激酶(MAPK)介导的途径组分RAF-MEK-ERK的异常激活,并且明显促进了肿瘤的发生。作为旨在寻找MAPK级联关键参与者B-Raf抑制剂的项目的一部分,我们最初确定了噻唑衍生物,该噻唑衍生物具有很高的效价和选择性,最佳的体外ADME特性,并且在啮齿动物中具有良好的药代动力学特征,但是患有高水平的hERG抑制活性。因此,进行了优化程序,主要集中在脚手架的R 1和R 2基团的加工上。这种努力最终导致了N-(4- 2-(1-环丙基哌啶-4-基)-4-4- [3-(2,5-二氟苯磺酰基氨基)-2-氟苯基]噻唑-5-基}-吡啶-2-基)乙酰胺(20),可保持良好的体外和体内特性,但缺乏hERG责任。除了仅对带有B-Raf V600E或V600D突变的细胞系表现出有效的抗增殖活性外,化合物20还令人感兴趣地显示,与其他已知的B-Raf抑制剂相比,非突变B