Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors
datasetposted on 2019-05-13, 00:00 authored by Marian C. Bryan, Joy Drobnick, Alberto Gobbi, Aleksandr Kolesnikov, Yongsheng Chen, Naomi Rajapaksa, Chudi Ndubaku, Jianwen Feng, Willy Chang, Ross Francis, Christine Yu, Edna F. Choo, Kevin DeMent, Yingqing Ran, Le An, Claire Emson, Zhiyu Huang, Swathi Sujatha-Bhaskar, Hans Brightbill, Antonio DiPasquale, Jonathan Maher, John Wai, Brent S. McKenzie, Patrick J. Lupardus, Ali A. Zarrin, James R. Kiefer
A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.