Design, synthesis and biological evaluation of novel pyrimidine and quinazoline-based small-molecule Toll-like...

Toll-like receptor 8 (TLR8) plays a key role in inflammatory and autoimmune disease pathogenesis. The development of TLR8 antagonists has therefore increased in recent years, however, no clinical candidates have yet reached the market. Here, we report a novel chemotype of selective TLR8 antagonists by replacing isoxazole with pyrimidine in previously reported isoxazole-based antagonists. Guided by an in-house building block library, pyrimidine-based compounds were synthesized and the most potent derivative 16 was biologically characterized. Further optimization via pyrimidine-benzene fusion led to the quinazoline derivative 35, which demonstrated high selectivity and significantly improved low nanomolar potency in inhibiting TLR8-mediated responses, comparable to the most potent antagonist reported to date. Computational and pharmacological studies indicated competitive binding within the chemical ligand-binding pocket at the TLR8 dimerization interface. Favorable physicochemical properties and good metabolic stability make compound 35 a promising lead structure for further chemical optimization into a potent TLR8 antagonist with therapeutic potential.