title: Structure-based drug design of tricyclic 8H-indeno[1,2-d][1,3]thiazoles as potent FBPase inhibitors.
abstract: With the goal of improving metabolic stability and further enhancing FBPase inhibitory activity, a series of tricyclic 8H-indeno[1,2-d][1,3]thiazoles was designed and synthesized with the aid of structure-based drug design. Extensive SAR studies led to the discovery of 19a with an IC(50) value of 1nM against human FBPase. X-ray crystallographic studies revealed that high affinity of 19a was due to the hydrophobic interaction arising from better shape complementarity and to the hydrogen bonding network involving the side chain on the tricyclic scaffold.
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: D018360:Crystallography, X-Ray; D015195:Drug Design; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D013844:Thiazoles; D006597:Fructose-Bisphosphatase