Lead optimization. Development of imatinib from a 2-phenylaminopyrimidine backbone (shown in white). (A) Activity in cellular assays was improved by introduction of a 3′ pyridyl group (yellow) at the 3′ position of the pyrimidine. (B) Activity against tyrosine kinases was further enhanced by addition of a benzamide group (orange) to the phenyl ring. (C) Attachment of a “flag-methyl” group (green) ortho to the diaminophenyl ring strongly reduced activity against PKC. (D) Addition of an N-methylpiperazine (purple) increased water solubility and oral bioavailability.