Structure−Activity Relationships for a Novel Series of Pyrido[2,3-<i>d</i>]pyrimidine Tyrosine Kinase Inhibitors

Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to the development of a novel series of ATP competitive pyrido[2,3-<i>d</i>]pyrimidine tyrosine kinase inhibitors. The initial lead, 1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-<i>d</i>]pyrimidin-7-yl]-3-<i>tert</i>-butylurea (<b>4b</b>, PD-089828), was found to be a broadly active tyrosine kinase inhibitor. Compound <b>4b</b> inhibited the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC<sub>50</sub> values of 1.11, 0.13, 0.45, and 0.22 μM, respectively. Subsequent SAR studies led to the synthesis of new analogs with improved potency, solubility, and bioavailability relative to the initial lead. For example, the introduction of a [4-(diethylamino)butyl]amino side chain into the 2-position of <b>4b</b> afforded compound <b>6c</b> with enhanced potency and bioavailability. Compound <b>6c </b>inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an IC<sub>50</sub> of 0.3 μM. Furthermore, replacement of the 6-(2,6-dichlorophenyl) moiety of <b>4b</b> with a 6-(3‘,5‘-dimethoxyphenyl) functionality produced a highly selective FGFr tyrosine kinase inhibitor <b>4e</b>. Compound <b>4e</b> inhibited the FGFr tyrosine kinase with an IC<sub>50</sub> of 0.060 μM, whereas IC<sub>50</sub>s for the inhibiton of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (<b>4e</b>) were all greater than 50 μM.