Structure鈥揂ctivity Relationships in Human Toll-like Receptor 8-Active 2,3-Diamino-furo[2,3-c]pyridines

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• 作者：Deepak B. Salunke ; Euna Yoo ; Nikunj M. Shukla ; Rajalakshmi Balakrishna ; Subbalakshmi S. Malladi ; Katelyn J. Serafin ; Victor W. Day ; Xinkun Wang ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 27, 2012
• 年：2012
• 卷：55
• 期：18
• 页码：8137-8151
• 全文大小：808K
• 年卷期：v.55,no.18(September 27, 2012)
• ISSN：1520-4804

文摘

In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke鈥揃lackburn鈥揃ienaym茅 multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3-c]pyridines, rather than the expected imidazo[1,2-a]pyridines, were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-魏B signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3-c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity.