2. Academic Validation
  3. 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

  • Eur J Med Chem. 2023 Oct 5;258:115616. doi: 10.1016/j.ejmech.2023.115616.
Yongjin Hao 1,  Jiawan Ma 1,  Jin Wang 1,  Xiaoliang Yu 2,  Zhanhui Li 1,  Shuwei Wu 3,  Sheng Tian 1,  Haikuo Ma 1,  Sudan He 4,  Xiaohu Zhang 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China.
  • 2 CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, 100005, PR China; Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: swwu@suda.edu.cn.
  • 4 CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, 100005, PR China; Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, PR China. Electronic address: hesd@ism.pumc.edu.cn.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: xiaohuzhang@suda.edu.cn.
PMID: 37413880 DOI: 10.1016/j.ejmech.2023.115616
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.

Keywords

IRAK4 inhibitor; Inflammation; Innate immunity; Pharmacokinetics; dihydrofuro[2,3-b]pyridine.

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