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Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors

Journal Article · · Journal of Medicinal Chemistry
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  1. Genentech, Inc., South San Francisco, CA (United States)
  2. WuXi Apptec, Shanghai (China)
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In this work, 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Sponsoring Organization:
Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; National Institutes of Health (NIH); USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231; AC02-06CH11357
OSTI ID:
1544868
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 13 Vol. 62; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES