Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position. Issue 11 (1st June 2016)

• Record Type: Journal Article
• Authors: Jordan, Allan M.; Begum, Habiba; Fairweather, Emma; Fritzl, Samantha; Goldberg, Kristin; Hopkins, Gemma V.; Hamilton, Niall M.; Lyons, Amanda J.; March, H. Nikki; Newton, Rebecca; Small, Helen F.; Vishwanath, Swamy; Waddell, Ian D.; Waszkowycz, Bohdan; Watson, Amanda J.; Ogilvie, Donald J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 11(2016)
• Page Start: 2724
• Page End: 2729
• Publication Date: 2016-06-01
• Subjects: Kinase inhibitor -- RET receptor -- Hepatocyte stability -- Targeted therapy -- Lung cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.03.100
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.