Synthesis and Biological Evaluation of 8-Oxoadenine Derivatives as Toll-like Receptor 7 Agonists Introducing the Antedrug Concept

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• 作者：Ayumu Kurimoto ; Kazuki Hashimoto ; Tomoaki Nakamura ; Kei Norimura ; Haruhisa Ogita ; Haruo Takaku ; Roger Bonnert ; Tom McInally ; Hiroki Wada ; Yoshiaki Isobe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 8, 2010
• 年：2010
• 卷：53
• 期：7
• 页码：2964-2972
• 全文大小：905K
• 年卷期：v.53,no.7(April 8, 2010)
• ISSN：1520-4804

文摘

Systemic administration of a Toll-like receptor 7 (TLR7) agonist is effective to in suppressing Th2 derived inflammation, however systemic induction of various cytokines such as IL-6, IL-12, and type I interferon (IFN) is observed. This cytokine induction would be expected to cause flu-like symptoms. We have previously reported adenine compounds (3, 4) as interferon inducing agents acting as TLR7 agonists. To identify potent anti-inflammatory compounds without systemic side effects, a labile carboxylic ester as an antedrug functionality onto the N(9)-benzyl group of the adenine was introduced. We found that 9e was a potent TLR7 agonist (EC₅₀ 50 nM) and rapidly metabolized by human plasma (T_1/2 2.6 min) to the pharmacologically much less active carboxylic acid 16. Intratracheal administration of 9e effectively inhibited allergen-induced airway inflammation without inducing cytokines systemically. Therefore, the TLR7 agonist with antedrug characteristics 9e (SM-324405) is a novel candidate for immunotherapy of allergic diseases.