期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 3, 页码 327-333出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00380
关键词
Benzolactam; IRAK4; Lupus; pyrazolopyrimidine
资金
- National Institutes of Health [S10_RR25528, S10_RR028976]
IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease.
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