Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity Naomi S. Rajapaksa Alberto Gobbi Joy Drobnick Steven Do Aleksandr Kolesnikov Jun Liang Yongsheng Chen Swathi Sujatha-Bhaskar Zhiyu Huang Hans Brightbill Ross Francis Christine Yu Edna F. Choo Kevin DeMent Yingqing Ran Le An Claire Emson Jonathan Maher John Wai Brent S. McKenzie Patrick J. Lupardus Ali A. Zarrin James R. Kiefer Marian C. Bryan 10.1021/acsmedchemlett.9b00380.s001 https://acs.figshare.com/articles/journal_contribution/Discovery_of_Potent_Benzolactam_IRAK4_Inhibitors_with_Robust_in_Vivo_Activity/10325036 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 <b>19</b> that achieves robust in vivo inhibition of cytokines relevant to human disease. 2019-11-18 22:16:25 IRAK 4. TLR blood assay benzolactam IRAK 4 inhibitors cytokine Potent Benzolactam IRAK 4 Inhibitors vivo inhibition IL -1Rs IRAK 4 inhibitors molecule 19 disease-relevant pharmacodynamic models Vivo Activity IRAK 4 kinase activity transduces dihydrobenzofuran inhibitors