Synthesis and evaluation of dihydrofuro[2,3-b]pyridine derivatives as potent IRAK4 inhibitors
Synthesis and evaluation of dihydrofuro[2,3-b]pyridine derivatives as potent IRAK4 inhibitors
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DOI：
10.1016/j.ejmech.2023.115616
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发表时间：
2023-07-04
影响因子：
6.7
通讯作者：
Zhang，Xiaohu
中科院分区：
文献类型：
--
作者：
Hao，Yongjin;Ma，Jiawan;Zhang，Xiaohu
白细胞介素-1受体相关激酶4（IRAK 4）是天然免疫应答中控制下游NF-κB和MAPK信号的关键调节因子，并且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]吡啶骨架的IRAK 4抑制剂。筛选命中16的结构修饰（IC 50 = 243 nM）导致IRAK 4抑制剂具有改善的效力，但具有高清除率（Cl）和差的口服生物利用度，如化合物21所例示的（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和减少确定的化合物38的清除率。化合物38显示出显著改善的清除率，同时保持针对IRAK 4的优异的生物化学效力（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减少小鼠iBMDM和人PBMC中促炎细胞因子的体外产生，并且在LPS诱导的小鼠模型中口服有效抑制血清TNF-α分泌。这些发现表明化合物38具有作为IRAK 4抑制剂用于治疗炎性和自身免疫性疾病的开发潜力。
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 hit16(IC50= 243 nM) led to IRAK4 inhibitors with improved potency but high clearance (Cl) and poor oral bioavailability, as exemplified by compound21(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 compound38. Compound38showed 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, compound38had favorablein vitrosafety and ADME profiles. Furthermore, compound38reduced thein vitroproduction 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 compound38has development potential as an IRAK4 inhibitor for the treatment of inflammatory and autoimmune disorders.