title: Synthesis, SAR, and X-ray structure of tricyclic compounds as potent FBPase inhibitors.
abstract: With the aim of discovering a novel class of fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of compounds based on tricyclic scaffolds was synthesized. Extensive SAR studies led to the finding of 8l with an IC50 value of 0.013 microM against human FBPase. An X-ray crystallographic study revealed that 8l bound at AMP binding sites of human liver FBPase with hydrogen bonding interactions similar to AMP.
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: Mizuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Takemoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Kanno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamane
authors.forename: Sayako
authors.initials: S
authors.lastname: Kawamura
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005943:Gluconeogenesis; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010755:Organophosphates; D063065:Organophosphonates; D006597:Fructose-Bisphosphatase