Synthesis and structure activity relationship studies of benzothieno[3,2-b]furan derivatives as a novel class of IKKbeta inhibitors.
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.
Sugiyama
Hideyuki
H
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. Sugiyama_Hideyuki@takeda.co.jp
Yoshida
Masato
M
Mori
Kouji
K
Kawamoto
Tomohiro
T
Sogabe
Satoshi
S
Takagi
Terufumi
T
Oki
Hideyuki
H
Tanaka
Toshimasa
T
Kimura
Hiroyuki
H
Ikeura
Yoshinori
Y
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
D004791:Enzyme Inhibitors; D005663:Furans; D051550:I-kappa B Kinase