Discovery of 5-Aryl-2,4-diaminopyrimidine Compounds as Potent and Selective IRAK4 Inhibitors

IRAK4 kinase plays a key role in TLR/IL-1Rsignaling pathways that regulate innate immune responses, and ifuncontrolled, it is responsible for various inflammatory disorders. Byhigh-throughput screening (HTS) and hit-to-lead optimization,compounds with a 5-aryl-2,4-diaminopyrimidine core structure havebeen identified as potent IRAK4 inhibitors. A cocrystal structure ofIRAK4 protein with an early lead molecule helped with under-standing the structure-activity relationship and the design of thenew compounds. Initial HTS hits from this series of compoundswere also found to inhibit TAK1 kinase, which would cause livertoxicity and potentially bone marrow failure. Optimization of thisseries resulted in improved selectivity over TAK1 kinase. The TAK1selectivity was found to be closely associated with different sizes andtypes of substituents at the 5-position of the pyrimidine. The impact of other pyrimidine substituents on the potency and selectivitywas also explored. A few representative compounds were evaluated in IL-1 beta-induced IL-6 inhibition animal model studies andshowed modest efficacy

Automated summary

IRAK4 kinase plays a crucial role in regulating innate immune responses and inhibiting its activity can help control inflammatory disorders. Through screening and optimizing compounds, potent IRAK4 inhibitors have been discovered, and the design of new compounds has been facilitated by analyzing the protein structure. Optimization of the compounds resulted in improved selectivity over TAK1 kinase. Some compounds showed modest efficacy in animal model studies.