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• W4382655402 endingPage "115616" @default.
• W4382655402 startingPage "115616" @default.
• W4382655402 abstract "Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key regulator to control downstream NF-κB and MAPK signals in the innate immune response and has been proposed as a therapeutic target for the treatment of inflammatory and autoimmune diseases. Herein, a series of IRAK4 inhibitors based on a dihydrofuro[2,3-b]pyridine scaffold was developed. Structural modifications of the screening hit 16 (IC50 = 243 nM) led to IRAK4 inhibitors with improved potency but high clearance (Cl) and poor oral bioavailability, as exemplified by compound 21 (IC50 = 6.2 nM, Cl = 43 ml/min/kg, F = 1.6%, LLE = 5.4). Structure modification aimed at improving LLE and reducing clearance identified compound 38. Compound 38 showed significantly improved clearance while maintained excellent biochemical potency against IRAK4 (IC50 = 7.3 nM, Cl = 12 ml/min/kg, F = 21%, LLE = 6.0). Importantly, compound 38 had favorable in vitro safety and ADME profiles. Furthermore, compound 38 reduced the in vitro production of pro-inflammatory cytokines in both mouse iBMDMs and human PBMCs and was orally efficacious in the inhibition of serum TNF-α secretion in LPS-induced mouse model. These findings suggested that compound 38 has development potential as an IRAK4 inhibitor for the treatment of inflammatory and autoimmune disorders." @default.
• W4382655402 created "2023-07-01" @default.
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• W4382655402 date "2023-10-01" @default.
• W4382655402 modified "2023-09-25" @default.
• W4382655402 title "Synthesis and evaluation of dihydrofuro[2,3-b]pyridine derivatives as potent IRAK4 inhibitors" @default.
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• W4382655402 doi "https://doi.org/10.1016/j.ejmech.2023.115616" @default.
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