Synergistic optimizations of efficacy and membrane permeability of IRAK4 inhibitors: identifying new lead compounds for anti-inflammatory therapeutics.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the N²,N⁴-diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based de novo design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (LogP), while also enforcing configurational constraints to enhance IRAK4-specific binding. Through iterative cycles of computational modelling and chemical synthesis, we identified 10 out of 17 newly synthesised compounds that exhibited potent IRAK4 inhibition at low-nanomolar concentrations in both enzymatic and cellular assays. Among these, compounds 10 and 13 stood out, demonstrating strong IRAK4 inhibitory activity, favourable membrane permeability, and minimal off-target kinase interactions.