Design and synthesis of novel 2,4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors

Abstract

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 IC₅₀ 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.

Graphical Abstract

KEYWORDS:

• Synthesis
• amino-pyrimidines
• T790M EGFR
• WT-EGFR
• cardiotoxicity

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors would like to thank ‘Science and Engineering Research Board (SERB) of Department of Science and Technology (DST) Govt. of India’ (Grant No. YSS/2015/002017) for funding the project.