title: A prodrug approach towards the development of tricyclic-based FBPase inhibitors.
abstract: For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.
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: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Jun
authors.initials: J
authors.lastname: Tanaka
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takagi
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: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000882:Haplorhini; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; D011725:Pyridines; D013844:Thiazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000409:Alanine