title: Synthesis and structure activity relationship studies of benzothieno[3,2-b]furan derivatives as a novel class of IKKbeta inhibitors.
abstract: As a novel class of IKKbeta inhibitors, a series of tricyclic furan derivatives was designed and synthesized based on the structure of known thiophene IKKbeta inhibitors. Among the various fused furan derivatives synthesized, a benzothieno[3,2-b]furan derivative 13a displayed potent inhibitory activity towards IKKbeta in enzymatic and cellular assays. The potent inhibitory activity originates from an intramolecular non-bonded S...O interaction which was confirmed by the X-ray structure of JNK3 with 16k. The introduction of further substituents on the core structure led to the discovery of the 6-alkoxy derivatives, which possessed a comparable IKKbeta inhibitory activity to 13a and an improved metabolic stability. Among these, appropriately lipophilic compounds 16a, h, i, and 13g (log D>2) were found to possess good oral bioavailability.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. Sugiyama_Hideyuki@takeda.co.jp
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kouji
authors.initials: K
authors.lastname: Mori
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikeura
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D051550:I-kappa B Kinase