Discovery of potent and orally active tricyclic-based FBPase inhibitors

  • Bioorg Med Chem. 2010 Jul 15;18(14):5346-51. doi: 10.1016/j.bmc.2010.05.041.
Tomoharu Tsukada  1 ,  Osamu Kanno ,  Takahiro Yamane ,  Jun Tanaka ,  Taishi Yoshida ,  Akira Okuno ,  Takeshi Shiiki ,  Mizuki Takahashi ,  Takahide Nishi
Affiliations
  • 1. Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 20542703 DOI: 10.1016/j.bmc.2010.05.041
Abstract

With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys.