Synthesis and structure activity relationship studies of benzothieno[3,2-b]furan derivatives as a novel class of IKKbeta inhibitors |
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Authors: | Sugiyama Hideyuki Yoshida Masato Mori Kouji Kawamoto Tomohiro Sogabe Satoshi Takagi Terufumi Oki Hideyuki Tanaka Toshimasa Kimura Hiroyuki Ikeura Yoshinori |
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Affiliation: | Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. Sugiyama_Hideyuki@takeda.co.jp |
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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. |
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