Replacing the terminal piperidine in ceritinib with aliphatic amines confers activities against crizotinib-resistant mutants including G1202R

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound <B>10</B> shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC<SUB>50</SUB> of 1.8 nM. Furthermore, pharmacokinetic profiles of <B>10</B> is apparently better than that of ceritinib. In murine xenograft studies, compound <B>10</B> turns out to be as active as ceritinib, suggesting that further optimization of <B>10</B> may lead to clinical candidates overcoming ALK mutant issues.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The terminal piperidine in ceritinib was replaced with diverse alkyl amines. </LI> <LI> Most of the analogs were as active as crizotinib against ALK wild-type and L1196M mutant. </LI> <LI> Compound <B>10</B> has excellent ALK mutant activities including extremely resistant G1202R. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>