Patel Harun, Ansari Azim, Pawara Rahul, Ansari Iqrar, Jadhav Harsha, Surana Sanjay
a Department of Pharmaceutical Chemistry , R. C. Patel Institute of Pharmaceutical Education and Research , Shirpur , India.
J Recept Signal Transduct Res. 2018 Oct-Dec;38(5-6):393-412. doi: 10.1080/10799893.2018.1557207.
Cardiotoxicity is one amongst the adverse effect of Osimertinib delineate in clinical trials and related to escalating doses. To triumph over the drawbacks of Osimertinib, in this study, we tend to delineate the design, synthesis, in vitro biological analysis of a series of novel reversible selective T790M inhibitors with minimal cardiotoxicity. Amongst the virtually sorted compounds; compound 18 and 74 have been located to be the foremost active compounds of the series with IC value of 0.88, 0.92 μM in cellular assay and 0.56, 0.62 μM in enzymatic assay, against double mutant L858R/T790M EGFR. Additionally, they showed much less affinity toward wild-type (WT)-EGFR with minimal cardiotoxicity.
心脏毒性是奥希替尼在临床试验中所描述的不良反应之一，且与剂量增加有关。为克服奥希替尼的缺点，在本研究中，我们描述了一系列具有最小心脏毒性的新型可逆性选择性T790M抑制剂的设计、合成及体外生物学分析。在几乎筛选的化合物中，化合物18和74被确定为该系列中活性最强的化合物，在细胞试验中对双突变L858R/T790M表皮生长因子受体（EGFR）的半数抑制浓度（IC）值为0.88、0.92μM，在酶试验中为0.56、0.62μM。此外，它们对野生型（WT）-EGFR的亲和力低得多，且心脏毒性最小。
