Chem. Pharm. Bull., 55(4),613-624, April 2007

Regular Articles

Synthesis and Structure Activity Relationship Studies of Benzothieno[3,2-b]furan Derivatives as a Novel Class of IKKβ Inhibitors

Hideyuki SUGIYAMA,^* Masato YOSHIDA, Kouji MORI, Tomohiro KAWAMOTO, Satoshi SOGABE, Terufumi TAKAGI, Hideyuki OKI, Toshimasa TANAKA, Hiroyuki KIMURA, and Yoshinori IKEURA

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited; 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. * To whom correspondence should be addressed. e-mail: Sugiyama_Hideyuki@takeda.co.jp

As a novel class of IKKβ inhibitors, a series of tricyclic furan derivatives was designed and synthesized based on the structure of known thiophene IKKβ inhibitors. Among the various fused furan derivatives synthesized, a benzothieno[3,2-b]furan derivative 13a displayed potent inhibitory activity towards IKKβ 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 IKKβ 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.

Key words IKK; kinase; inhibitor; benzothieno[3,2-b]furan; non-bonded interaction