Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors
| Autor: | Patrick J. Lupardus, Yongsheng Chen, Naomi S. Rajapaksa, John S. Wai, Kevin DeMent, Edna F. Choo, Brent S. McKenzie, Ross Francis, Joy Drobnick, Hans Brightbill, James R. Kiefer, Willy M. Chang, Chudi Ndubaku, Alberto Gobbi, Antonio G. DiPasquale, Aleksandr Kolesnikov, Jonathan Maher, Jianwen Feng, Claire Emson, Le An, Ali A. Zarrin, Zhiyu Huang, Christine Yu, Yingqing Ran, Marian C. Bryan, Swathi Sujatha-Bhaskar |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
01 natural sciences
Cocrystal Pyrazolopyrimidine 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship In vivo Catalytic Domain Drug Discovery Potency Structure–activity relationship Animals Humans Protein Kinase Inhibitors 030304 developmental biology Benzofurans 0303 health sciences Bicyclic molecule Molecular Structure Chemistry IRAK4 Combinatorial chemistry 0104 chemical sciences Rats Mice Inbred C57BL 010404 medicinal & biomolecular chemistry Interleukin-1 Receptor-Associated Kinases Pyrimidines Aminoquinolines Molecular Medicine Pyrazoles Female Selectivity Protein Binding Signal Transduction |
| Zdroj: | Journal of medicinal chemistry. 62(13) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|