喹啉
TLR7型
化学
药理学
药物化学
计算机科学
组合化学
受体
立体化学
生物化学
有机化学
医学
先天免疫系统
Toll样受体
作者
Emma G. DeYoung,Justin M. Howe,Siteng Fang,Mullapudi Mohan Reddy,Jillian P. Handel,Jared T. Miller,Daniel R. Wheeler,L. Nathan Tumey
标识
DOI:10.1021/acsmedchemlett.3c00260
摘要
TLR7 agonists have significant therapeutic potential in a variety of oncology and autoimmune applications. We recently reported a potent TLR7 selective agonist 1 that could be delivered by antibody–drug conjugate (ADC) technology to elicit potent anticancer activity. Herein we report synthetic chemistry and structure–activity relationship studies to develop TLR7 agonists with improved potency for next-generation ADC efforts. We found that the addition of hydrophobic acyl tails to parent compound 1 generally resulted in retained or improved TLR7 agonist activity without sacrificing the permeability or the selectivity over TLR8. In contrast, the addition of a simple alkyl tail at the same position resulted in a dramatic loss in potency. Molecular modeling was performed to provide a rationale for this dramatic loss in potency. We ultimately identified compounds 17b, 16b, and 16d as highly potent TLR7 agonists that potently induced the activation of mouse macrophages and hPBMCs at low-nanomolar concentrations.
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