Structure–Activity Relationship Analysis of Imidazoquinolines with Toll-like Receptors 7 and 8 Selectivity and Enhanced Cytokine Induction

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• 作者：Charles E. Schiaffo ; Ce Shi ; Zhengming Xiong ; Michael Olin ; John R. Ohlfest ; Courtney C. Aldrich ; David M. Ferguson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 23, 2014
• 年：2014
• 卷：57
• 期：2
• 页码：339-347
• 全文大小：412K
• ISSN：1520-4804

文摘

Toll-like receptors 7 and 8 (TLRs) have emerged as key targets in the design of small molecule adjuvants and stimulants for use in immunotherapies. This study examines the structure鈥揳ctivity relationship of a series of C2- and N1-substituted C7-methoxycarbonylimidazoquinolines to gain insight to the structural basis to TLR-7 and -8 selective activity. The analysis is further applied to evaluate the induction of multiple cytokines, including IL-10, IL-12, IL-1尾, TNF-伪, IFN-伪, and IFN-纬, using murine BMDCs and human PBMCs. The results show TLR-7/8 activity is correlated to the C2-alkyl chain length, with peak activity occurring for the butyl (TLR-7) and pentyl (TLR-8) derivatives. A similar SAR is identified in the production of IL-1尾, IL-12, and IFN-纬, which are shown to depend on both the C2-alkyl chain length and substitution to the N1-position. The compounds were also potent stimulators of IFN-伪 and IL-10 production but with less pronounced structure-based correlations.