Synthesis, structure-activity relationship studies and evaluation of a TLR 3/8/9 agonist and its analogues

A comprehensive SAR study of a putative TLR 3/8/9 agonist was conducted. Despite the excitement surrounding the potential of the first small molecule TLR3 agonist with a compound that additionally displayed agonist activity for TLR8 and TLR9, compound 1 displayed disappointing activity in our hands, failing to match the potency (EC50) reported and displaying only a low efficacy for the extent of stimulated NF-kappa B activation and release. The evaluation of >75 analogs of 1, many of which constitute minor modifications in the structure, failed to identify any that displayed significant activity and none that exceeded the modest activity found for 1. [GRAPHICS] .

Automated summary

The comprehensive SAR study of a putative TLR 3/8/9 agonist did not meet the expected activity levels. Evaluation of over 75 analogs failed to identify any with significant activity, with none surpassing the modest activity of the original compound.