Open AccessDiscovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors
Author(s) -
W. Michael Seganish,
Thierry O. Fischmann,
Bradley Sherborne,
Julius J. Matasi,
Brian J. Lavey,
William T. McElroy,
Deen Tulshian,
Jim Tata,
Christopher Sondey,
Charles G. Garlisi,
Kristine Devito,
James Fossetta,
Dan Lundell,
Xiaoda Niu
Publication year - 2015
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.5b00279
Subject(s) - chemotype , kinase , ic50 , chemistry , high throughput screening , combinatorial chemistry , bioavailability , pharmacology , biochemistry , in vitro , biology , chromatography , essential oil
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%).