Synthesis and evaluation of dihydrofuro[2,3-b]pyridine derivatives as potent IRAK4 inhibitors

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.

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