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Fig. 3 | Journal of Hematology & Oncology

Fig. 3

From: Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy

Fig. 3

Chemical optimization and functions of imatinib structure. The phenylaminopyrimidine derivative lead compound is indicated in black. ① The pyridyl group (red) added at 3′-position of the pyrimidine moiety enhanced cellular activity, ② the amide substituent (blue) on the phenyl ring provided the molecule with inhibitory activity against tyrosine kinases, and ③ the 6-methyl (green) addition to the central aminophenyl ring nullified the unspecific activity on PKC, thus increasing selectivity of the compound for Bcr-Abl. Finally, ④ an N-methylpiperazine (purple) was added to enhance aqueous solubility and oral bioavailability of the drug, but ⑤ required the insertion of the amide linker and a benzene ring (yellow) as a spacer to abolish the mutagenic potential of the aniline moiety otherwise obtained. Imatinib was therefore developed as optimized Bcr-Abl oral inhibitor

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