Discovery of potent and orally active tricyclic-based FBPase inhibitors

Tomoharu Tsukada; Osamu Kanno; Takahiro Yamane; Jun Tanaka; Taishi Yoshida; Akira Okuno; Takeshi Shiiki; Mizuki Takahashi; Takahide Nishi

doi:10.1016/j.bmc.2010.05.041

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. Epub 2010 May 20.

Authors

Tomoharu Tsukada¹, Osamu Kanno, Takahiro Yamane, Jun Tanaka, Taishi Yoshida, Akira Okuno, Takeshi Shiiki, Mizuki Takahashi, Takahide Nishi

Affiliation

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.

MeSH terms

Administration, Oral
Animals
Blood Glucose / metabolism
Cells, Cultured
Crystallography, X-Ray
Diabetes Mellitus, Type 2 / drug therapy
Drug Design
Fructose-Bisphosphatase / antagonists & inhibitors*
Fructose-Bisphosphatase / chemistry
Fructose-Bisphosphatase / metabolism*
Glucose / antagonists & inhibitors*
Hepatocytes / metabolism
Humans
Macaca fascicularis
Models, Molecular
Organophosphonates / chemical synthesis
Organophosphonates / chemistry
Organophosphonates / pharmacology*
Prodrugs / chemical synthesis
Prodrugs / chemistry
Prodrugs / pharmacology*

Substances

Blood Glucose
Organophosphonates
Prodrugs
Fructose-Bisphosphatase
Glucose