Neutral 5-substituted 4-indazolylaminoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase

Abstract

We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

“…AZD1719 (compound 19) was one such compound that arose from this work, although this compound was ultimately halted because of adverse preclinical safety findings judged to be off-target. As above, the medicinal chemistry of this discovery has previously been disclosed, although does not specifically refer to AZD1719, which is designated compound Q10 22 in this referenced work [41].…”

Regioselective Suzuki-Miyaura Reaction: Application to the Microwave-promoted Synthesis of 4,7-Diarylquinazolines

“…Especially, their importance as selective anticancer chemotherapy agents appears unparalleled and attracts the attention of many pharmaceutical research teams worldwide [10][11][12][13]. Focusing on quinazoline substrates, our group also quite recently described the preparation of new 2-substituted-quinazoline derivatives which exhibit original antiplasmodial properties [14][15][16].…”

A first synthesis of 18F‐radiolabeled lapatinib: a potential tracer for positron emission tomographic imaging of ErbB1/ErbB2 tyrosine kinase activity

“…Inhibition of epidermal growth factor receptor tyrosine kinases, which are often overexpressed in tumors, is an attractive modern approach to cancer therapeutics and is an area of active investigations. Many drugs to inhibit tyrosine kinase activity have been developed or are under development . Molecular probes and radiolabeled analogs of epidermal growth factor receptor tyrosine kinase inhibitor drugs engender multiple interests including studies of basic mechanisms of action, preclinical targeting studies, and further drug development for new indications in oncology.…”