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.

Interleukin-1 受体相关激酶 4 (IRAK4) 是先天免疫反应中控制下游 NF-κB 和 MAPK 信号的关键调节因子，已被提议作为治疗炎症和自身免疫性疾病的治疗靶点。在此，开发了一系列基于二氢呋喃并[2,3- b ]吡啶支架的IRAK4抑制剂。筛选命中16 (IC ₅₀  = 243 nM) 的结构修饰导致 IRAK4 抑制剂的效力提高，但清除率 (Cl) 高且口服生物利用度差，如化合物21 (IC ₅₀  = 6.2 nM，Cl = 43 ml/min) /kg，F = 1.6%，LLE = 5.4)。结构修饰旨在改善 LLE 并减少已确定的化合物38 的间隙。化合物38显示出显着改善的清除率，同时保持优异的针对IRAK4的生化效力（IC ₅₀  = 7.3 nM，Cl = 12 ml/min/kg，F = 21%，LLE = 6.0）。重要的是，化合物38具有良好的体外安全性和 ADME 特征。此外，化合物38可以减少小鼠 iBMDM 和人 PBMC 中促炎细胞因子的体外产生，并且口服可有效抑制 LPS 诱导的小鼠模型中血清 TNF-α 的分泌。这些发现表明化合物38具有作为 IRAK4 抑制剂治疗炎症和自身免疫性疾病的开发潜力。