期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 13, 页码 6223-6240出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00439
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资金
- DOE Office of Science [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085131000817]
- National Institutes of Health [S10_RR25528, S10_RR028976]
- Howard Hughes Medical Institute
- Department of Energy Office of Science User Facility [DE-AC02-05CH11231]
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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