jm9b00439_si_002.csv (2.2 kB)
Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors
dataset
posted 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. KieferA 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.
