Tyrosine kinase inhibitors. 12. Synthesis and structure-activity relationships for 6-substituted 4-(phenylamino)pyrimido[5,4-d]pyrimidines designed as inhibitors of the epidermal growth factor receptor

Journal of Medicinal Chemistry
G W RewcastleW A Denny

Abstract

A series of 6-substituted 4-anilinopyrimido[5,4-d]pyrimidines has been prepared and shown to be potent inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). These compounds are structurally related to the pyrido[3,2-d]- and pyrido[3,4-d]-pyrimidines previously shown to be EGFR inhibitors. Their structure-activity relationships (SAR) for inhibition of the isolated enzyme more closely resemble those of the [3,2-d] than the [3,4-d] pyridopyrimidine isomers. This suggests the requirement of an aza atom in the 7- but not the 5-position (i.e., a carbon atom in the 5-position) for the enhanced potency shown by 6-N-methylated derivatives in each series. X-ray crystal structures were determined for the three NHMe derivatives 2, 3, and 5c in the pyrido[9,2-d]-, pyrido[3,4-d]-, and pyrimido[5,4-d]-pyrimidine series, respectively. These show that a carbon rather than a nitrogen atom at the 5-position leads to significant conformational changes in the molecule (a longer C5a-C4 bond and a 30 degrees out-of-plane rotation of the phenyl group), due to the requirement to relieve nonbonding interactions between the C5 and N9 protons. Pyrimido[5,4-d]pyrimidine analogues bearing bulky, weakly basic solubilizing...Continue Reading

References

Jan 1, 1987·Methods in Enzymology·D Barnes
Jan 1, 1995·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·G FontaniniG Bevilacqua
Jan 1, 1996·Breast Cancer Research and Treatment·A E WakelingJ R Woodburn

❮ Previous
Next ❯

Citations

Oct 19, 2001·Medicinal Research Reviews·P TraxlerJ Zimmermann
Apr 15, 2004·Bioorganic & Medicinal Chemistry·Gang ChenHualiang Jiang
Mar 22, 2003·Experimental Cell Research·David W Fry
Aug 24, 1999·Pharmacology & Therapeutics·P Traxler, P Furet
Oct 7, 2003·Bioorganic & Medicinal Chemistry·Aparna VemaGautam R Desiraju
Mar 15, 2011·SAR and QSAR in Environmental Research·A K GuptaA K Saxena
Nov 26, 2008·Acta Pharmacologica Sinica·Hai-hong LiHong Liu
Mar 1, 2013·Journal of Advanced Research·Wafaa S HamamaHanafi H Zoorob
Feb 3, 2005·Bioorganic & Medicinal Chemistry Letters·Zakaria RachidBertrand Jacques Jean-Claude
Jun 22, 2006·Medicinal Research Reviews·Shantaram Kamath, John K Buolamwini
Jun 25, 2008·Archiv der Pharmazie·Pandey K Sarvesh, Khan Nizamuddin
Jun 21, 2017·BioMed Research International·Manman ZhaoBing Niu
Dec 23, 1999·Medicinal Research Reviews·C García-EcheverríaD B Evans
Jan 28, 2020·Current Organic Synthesis·Mohamed MonierKhaled M Elattar
Jan 5, 2001·Bioorganic & Medicinal Chemistry Letters·S W WrightP H Bauer
May 12, 2009·Journal of Combinatorial Chemistry·Ramin GhahremanzadehAyoob Bazgir
Jan 28, 2003·Journal of Chemical Information and Computer Sciences·Tao PengJiaju Zhou
Oct 17, 2003·Journal of Medicinal Chemistry·David J Diller, Rixin Li
Sep 19, 2003·Journal of Medicinal Chemistry·Zakaria RachidBertrand J Jean-Claude
Jan 21, 2011·ACS Combinatorial Science·Ghazaleh Imani ShakibaeiAyoob Bazgir
Mar 12, 2011·The Journal of Organic Chemistry·Rui ZhangDewen Dong
Dec 29, 2000·Journal of Chemical Information and Computer Sciences·B Pirard, S D Pickett
Dec 26, 2001·Chemical Reviews·A J Bridges

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2021 Meta ULC. All rights reserved