On February 26, 1998, Rewcastle, Gordon W.; Murray, Donna K.; Elliott, William L.; Fry, David W.; Howard, Curtis T.; Nelson, James M.; Roberts, Billy J.; Vincent, Patrick W.; Showalter, H. D. Hollis; Winters, R. Thomas; Denny, William A. published an article.Formula: C7H3ClFN3 The title of the article was Tyrosine Kinase Inhibitors. 14. Structure-Activity Relationships for Methyl- amino-Substituted Derivatives of 4-[(3-Bromophenyl)amino]-6-(methylamino)- pyrido[3,4-d]pyrimidine (PD 158780), a Potent and Specific Inhibitor of the Tyrosine Kinase Activity of Receptors for the EGF Family of Growth Factors. And the article contained the following:
PD 158780 (I) is a very potent in vitro inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (IC50 = 0.08 nM), and other members of the erbB family, by competitive binding at the ATP site of these signal transduction enzymes. A series of analogs of PD 158780 bearing solubilizing functions off the 6-methylamino substituent were prepared by reaction of the 6-fluoro derivatives with appropriate amine nucleophiles. These were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF-stimulated full-length EGFR enzyme and for inhibition of autophosphorylation of the EGFR in A431 human epidermoid carcinoma cells in culture. The most effective analogs were those bearing weakly basic substituents through a secondary amine linkage, which proved water-soluble (>10 mM) and potent (IC50s generally <1 nM). No clear SAR could be discerned for these compounds with respect to amine base strength or the distance of the cationic center from the chromophore, suggesting that 6-substituents are in a favorable area of bulk tolerance in the enzyme binding site. More distinct SAR emerged for the ability of the compounds to inhibit EGFR autophosphorylation in A431 cells, where analogs bearing lipophilic weak bases were preferred. Representative analogs were evaluated for antitumor effectiveness against four in vivo tumor models. Significant in vivo activity was observed in estrogen-dependent MCF-7 breast and A431 epidermoid tumors. Marginal activity was seen in an EGFR-transfected tumor model, suggesting that while this cell line requires EGF for clone formation in soft agar, other growth factors may be able to replace EGF in vivo. Also, activity was seen against the SK-OV-3 ovarian cancer model, which is known to express other EGF receptor family members (although it is not clear whether these are absolutely required for growth in vivo). While substantial growth delays were seen in A431 and MCF-7 tumor models, the treated tumors remained approx. the same size throughout therapy, suggesting that the compounds are cytostatic rather than cytotoxic under these test conditions. It remains to be determined if more prolonged therapy has cytotoxic effects in vivo, resulting in net tumor cell kill. The experimental process involved the reaction of 4-Chloro-6-fluoropyrido[3,4-d]pyrimidine(cas: 175357-98-9).Formula: C7H3ClFN3
The Article related to pd 158780 analog preparation structure activity, antitumor activity pd 158780 analog preparation, tyrosine kinase inhibitor pd 158780 analog, autophosphorylation inhibitor pd 158780 analog preparation, epidermal growth factor receptor inhibitor preparation and other aspects.Formula: C7H3ClFN3
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia