Discovery of potent and orally active tricyclic-based FBPase inhibitors.
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.
Tsukada
Tomoharu
T
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Kanno
Osamu
O
Yamane
Takahiro
T
Tanaka
Jun
J
Yoshida
Taishi
T
Okuno
Akira
A
Shiiki
Takeshi
T
Takahashi
Mizuki
M
Nishi
Takahide
T
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D001786:Blood Glucose; D063065:Organophosphonates; D011355:Prodrugs; D006597:Fructose-Bisphosphatase; D005947:Glucose