Journal of Medicinal Chemistry p. 6223 - 6240 (2019)
Update date:2022-08-15
Topics:
Bryan, Marian C.
Drobnick, Joy
Gobbi, Alberto
Kolesnikov, Aleksandr
Chen, Yongsheng
Rajapaksa, Naomi
Ndubaku, Chudi
Feng, Jianwen
Chang, Willy
Francis, Ross
Yu, Christine
Choo, Edna F.
Dement, Kevin
Ran, Yingqing
An, Le
Emson, Claire
Huang, Zhiyu
Sujatha-Bhaskar, Swathi
Brightbill, Hans
Dipasquale, Antonio
Maher, Jonathan
Wai, John
McKenzie, Brent S.
Lupardus, Patrick J.
Zarrin, Ali A.
Kiefer, James R.
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.
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