1. Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.
- Author
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Bryan MC, Drobnick J, Gobbi A, Kolesnikov A, Chen Y, Rajapaksa N, Ndubaku C, Feng J, Chang W, Francis R, Yu C, Choo EF, DeMent K, Ran Y, An L, Emson C, Huang Z, Sujatha-Bhaskar S, Brightbill H, DiPasquale A, Maher J, Wai J, McKenzie BS, Lupardus PJ, Zarrin AA, and Kiefer JR
- Subjects
- Aminoquinolines chemical synthesis, Aminoquinolines metabolism, Aminoquinolines pharmacology, Animals, Benzofurans chemical synthesis, Benzofurans metabolism, Benzofurans pharmacology, Catalytic Domain, Female, Humans, Interleukin-1 Receptor-Associated Kinases metabolism, Mice, Inbred C57BL, Molecular Structure, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Pyrazoles chemical synthesis, Pyrazoles metabolism, Pyrimidines chemical synthesis, Pyrimidines metabolism, Rats, Signal Transduction drug effects, Structure-Activity Relationship, Interleukin-1 Receptor-Associated Kinases antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology
- Abstract
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.
- Published
- 2019
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