Details

Autor(en) / Beteiligte

• Aoki, Toshihiro
• Hyohdoh, Ikumi
• Furuichi, Noriyuki
• Ozawa, Sawako
• Watanabe, Fumio
• Matsushita, Masayuki
• Sakaitani, Masahiro
• Morikami, Kenji
• Takanashi, Kenji
• Harada, Naoki
• Tomii, Yasushi
• Shiraki, Koji
• Furumoto, Kentaro
• Tabo, Mitsuyasu
• Yoshinari, Kiyoshi
• Ori, Kazutomo
• Aoki, Yuko
• Shimma, Nobuo
• Iikura, Hitoshi

Titel

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning

Ist Teil von

• ACS medicinal chemistry letters, 2014-04, Vol.5 (4), p.309-314

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Electronic Journals Library - Freely accessible e-journals

Beschreibungen/Notizen

• Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.