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Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.

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.

SUBMITTER: Jordan AM

PROVIDER: S-EPMC4896930 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.

Jordan Allan M AM Begum Habiba H Fairweather Emma E Fritzl Samantha S Goldberg Kristin K Hopkins Gemma V GV Hamilton Niall M NM Lyons Amanda J AJ March H Nikki HN Newton Rebecca R Small Helen F HF Vishwanath Swamy S Waddell Ian D ID Waszkowycz Bohdan B Watson Amanda J AJ Ogilvie Donald J DJ

Bioorganic & medicinal chemistry letters 20160330 11

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 prov ...[more]

PMID: 27086121

Dataset Information

Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.

Publications

Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.

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