Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility

  • Bioorg Med Chem Lett. 2013 Feb 1;23(3):669-72. doi: 10.1016/j.bmcl.2012.11.114.
Tomoaki Nakamura  1 ,  Hiroki Wada ,  Hirotaka Kurebayashi ,  Tom McInally ,  Roger Bonnert ,  Yoshiaki Isobe
Affiliations
  • 1. Chemistry Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd, 3-1-98 Kasagade-naka, Osaka-city, Osaka 554-0022, Japan.
PMID: 23265901 DOI: 10.1016/j.bmcl.2012.11.114
Abstract

We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model.

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