絞り込み

16603

広告

Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties.

著者 Lei H , Jiang N , Miao X , Xing L , Guo M , Liu Y , Xu H , Gong P , Zuo D , Zhai X
Eur J Med Chem.2019 Mar 23 ; 171():297-309.
この記事をPubMed上で見るPubMedで表示
この記事をGoogle翻訳上で見る Google翻訳で開く

スターを付ける スターを付ける     (20view , 0users)

Full Text Sources

Miscellaneous

Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6-33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15 showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3, with IC values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALK and ALK mutants with IC values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profiles of 15 were obtained with quite satisfying AUC and C values. Besides, the binding models of 15 with ALK, ALK and ROS1 clearly present the essential interactions within the active site.
PMID: 30927566 [PubMed - as supplied by publisher]
印刷用ページを開く Endnote用テキストダウンロード