Newton, Rebecca published the artcileThe discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity, Quality Control of 14703-69-6, the publication is European Journal of Medicinal Chemistry (2016), 20-32, database is CAplus and MEDLINE.
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clin. approved multi-kinase inhibitors that target RET as a secondary pharmacol. but addnl. activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clin. need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
European Journal of Medicinal Chemistry published new progress about 14703-69-6. 14703-69-6 belongs to alcohols-buliding-blocks, auxiliary class Amine,Benzene,Phenol, name is 3-(Methylamino)phenol, and the molecular formula is C7H9NO, Quality Control of 14703-69-6.
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