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Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors.

ABSTRACT: We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).

SUBMITTER: Seganish WM

PROVIDER: S-EPMC4538434 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors.

Seganish W Michael WM Fischmann Thierry O TO Sherborne Brad B Matasi Julius J Lavey Brian B McElroy William T WT Tulshian Deen D Tata James J Sondey Christopher C Garlisi Charles G CG Devito Kristine K Fossetta James J Lundell Daniel D Niu Xiaoda X

ACS medicinal chemistry letters 20150712 8

We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displa ...[more]

PMID: 26288698

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