In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure–activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.

中文翻译：

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基于四氢吡啶并嘧啶的Toll样受体（TLR）7/8双激动剂的设计与合成

在发现新的TLR激动剂的不断努力中，我们在此报告了新型四氢吡啶并嘧啶TLR 7/8激动剂的发现及其构效关系。该系列化合物的双重激动剂活性和高清除率的优化导致了化合物52a1的鉴定。体内评估显示，全身暴露受限的小鼠体内存在干扰素刺激反应（ISG），并显示出抗病毒治疗或作为疫苗佐剂的潜力。