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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Aminoquinolines / chemical synthesis
-
Aminoquinolines / metabolism
-
Aminoquinolines / pharmacology
-
Animals
-
Benzofurans / chemical synthesis
-
Benzofurans / metabolism
-
Benzofurans / pharmacology
-
Catalytic Domain
-
Female
-
Humans
-
Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
-
Interleukin-1 Receptor-Associated Kinases / metabolism
-
Mice, Inbred C57BL
-
Molecular Structure
-
Protein Binding
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / metabolism
-
Protein Kinase Inhibitors / pharmacology*
-
Pyrazoles / chemical synthesis
-
Pyrazoles / metabolism
-
Pyrazoles / pharmacology*
-
Pyrimidines / chemical synthesis
-
Pyrimidines / metabolism
-
Pyrimidines / pharmacology*
-
Rats
-
Signal Transduction / drug effects
-
Structure-Activity Relationship
Substances
-
Aminoquinolines
-
Benzofurans
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrimidines
-
Interleukin-1 Receptor-Associated Kinases
-
Irak4 protein, mouse