title: Discovery of potent and orally active tricyclic-based FBPase inhibitors.
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.
authors.affiliation: Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Tsukada
authors.forename: Osamu
authors.initials: O
authors.lastname: Kanno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamane
authors.forename: Jun
authors.initials: J
authors.lastname: Tanaka
authors.forename: Taishi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Okuno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiiki
authors.forename: Mizuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: 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*
chemical_list: D001786:Blood Glucose; D063065:Organophosphonates; D011355:Prodrugs; D006597:Fructose-Bisphosphatase; D005947:Glucose