Synthesis and Structure Activity Relationship Studies of Benzothieno[3,2-b]furan Derivatives as a Novel Class of IKK.BETA. Inhibitors
| Autor: | Toshimasa Tanaka, Hiroyuki Kimura, Satoshi Sogabe, Hideyuki Sugiyama, Tomohiro Kawamoto, Terufumi Takagi, Masato Yoshida, Kouji Mori, Hideyuki Oki, Yoshinori Ikeura |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular chemistry.chemical_classification Magnetic Resonance Spectroscopy Stereochemistry Kinase General Chemistry General Medicine I-kappa B Kinase Bioavailability Structure-Activity Relationship chemistry.chemical_compound Enzyme chemistry Furan Intramolecular force Drug Discovery Thiophene Structure–activity relationship Enzyme Inhibitors Furans Tricyclic |
| Zdroj: | Chemical and Pharmaceutical Bulletin. 55:613-624 |
| ISSN: | 1347-5223 0009-2363 |
| DOI: | 10.1248/cpb.55.613 |
| Popis: | 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 D2) were found to possess good oral bioavailability. |
| Databáze: | OpenAIRE |
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