Synthesis, SAR, and X-ray structure of tricyclic compounds as potent FBPase inhibitors.
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.
Tsukada
Tomoharu
T
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Takahashi
Mizuki
M
Takemoto
Toshiyasu
T
Kanno
Osamu
O
Yamane
Takahiro
T
Kawamura
Sayako
S
Nishi
Takahide
T
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
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010755:Organophosphates; D063065:Organophosphonates; D006597:Fructose-Bisphosphatase