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 Facto

doi:10.1021/JM970641D

Paper

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 Facto

Published Feb 3, 1998 · G. Rewcastle, D. Murray, W. Elliott

Journal of Medicinal Chemistry

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95

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Abstract

The 4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine PD 158780 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 analogues 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 analogues 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 o...

In Vitro Study

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Methyl-amino-substituted derivatives of PD 158780 show potent and specific inhibition of tyrosine kinase activity in growth factor receptors, with potential for use in cancer therapy.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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References

Citations

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Recent Developments in the MCRs Synthesis of Pyridopyrimidines and Spiro-Pyridopyrimidines

Recent developments in multi-component synthesis of pyridopyrimidine and spiro-conjugated pyridopyrimidine systems show promise for biological and medicinal applications.

18F-Labeled Pyrido[3,4-d]pyrimidine as an Effective Probe for Imaging of L858R Mutant Epidermal Growth Factor Receptor.

[18F]APP-1 effectively visualizes L858R mutant EGFR in nonsmall-cell lung carcinoma tumors, aiding in the prediction of drug resistance and guiding targeted therapy.

EGFr, FGFr and PDGFr: Emerging Targets for Anticancer Drug Design

EGFr, FGFr, and PDGFr tyrosine protein kinases are emerging targets for developing less toxic anticancer drugs with potential benefits for treating various cancers.

Spiroanthraceneoxazolidine as a synthetic equivalent of methanimine in the reaction with donor–acceptor cyclopropanes. Synthesis of diethyl 5-arylpyrrolidine-3,3-dicarboxylates

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Synthesis and antiproliferative evaluation of novel tetrahydrobenzo[4′,5′]thieno[3′,2′:5,6]pyrido[4,3-d] pyrimidine derivatives

Novel tetrahydrobenzo[4′,5′]thieno[3′,2′:5,6]pyrido[4,3-d] pyrimidine derivatives show strong antiproliferative activity against KB and CEN2 cell lines, with compound 7a showing the highest

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This study demonstrates the synthesis and transformation of 1,3-thiazolo(thiazino)-fused pyrido[3,4-d]pyrimidines, providing insights into their chemistry and applications.