Zhang, Haoyang; Wu, Wenkui; Feng, Chao; Liu, Zhaogang; Bai, Enhe; Wang, Xueyuan; Lei, Meng; Cheng, Hao; Feng, Huayun; Shi, Jingmiao; Wang, Jia; Zhang, Zhao; Jin, Tao; Chen, Shanshan; Hu, Shihe; Zhu, Yongqiang published the artcile< Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants>, Application In Synthesis of 5018-38-2, the main research area is dihydropyrroloquinoline preparation anticancer EGFR modulator; 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives; EGFR modulator; L858R/T790M double mutants; Non-small cell lung cancer.
Based upon the modeling binding mode of marketed AZD9291 (I) with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound II showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound II exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.
European Journal of Medicinal Chemistry published new progress about Antitumor agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Application In Synthesis of 5018-38-2.
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia