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Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity

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journal contribution
posted on 2019-11-18, 22:16 authored by 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
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.