1218987-98-4Relevant academic research and scientific papers
Synthesis and biological evaluation of 8-oxoadenine derivatives as toll-like receptor 7 agonists introducing the antedrug concept
Kurimoto, Ayumu,Hashimoto, Kazuki,Nakamura, Tomoaki,Norimura, Kei,Ogita, Haruhisa,Takaku, Haruo,Bonnert, Roger,McInally, Tom,Wada, Hiroki,Isobe, Yoshiaki
experimental part, p. 2964 - 2972 (2010/08/05)
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 (T1/2 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.
