Synthesis and biological evaluation of 8-oxoadenine derivatives as toll-like receptor 7 agonists introducing the antedrug concept.
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 (EC(50) 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.
Chemistry Research II, Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasagade-naka, Konahana-ku, Osaka 554-0022, Japan. ayumu-kurimoto@ds-pharma.co.jp
Ayumu
A
Kurimoto
Kazuki
K
Hashimoto
Tomoaki
T
Nakamura
Kei
K
Norimura
Haruhisa
H
Ogita
Haruo
H
Takaku
Roger
R
Bonnert
Tom
T
McInally
Hiroki
H
Wada
Yoshiaki
Y
Isobe
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D004355:Drug Stability; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism / Q000628:therapy; D007167:Immunotherapy; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007372:Interferons / Q000096:biosynthesis; D008297:Male; D051381:Rats; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism
D002264:Carboxylic Acids; D051199:Toll-Like Receptor 7; C002992:8-hydroxyadenine; D007372:Interferons; D000225:Adenine