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

  • ACS Med Chem Lett. 2014 Jan 22;5(4):309-14. doi: 10.1021/ml400379x.
Toshihiro Aoki  1 ,  Ikumi Hyohdoh  1 ,  Noriyuki Furuichi  1 ,  Sawako Ozawa  1 ,  Fumio Watanabe  1 ,  Masayuki Matsushita  1 ,  Masahiro Sakaitani  1 ,  Kenji Morikami  2 ,  Kenji Takanashi  1 ,  Naoki Harada  1 ,  Yasushi Tomii  1 ,  Koji Shiraki  2 ,  Kentaro Furumoto  2 ,  Mitsuyasu Tabo  2 ,  Kiyoshi Yoshinari  1 ,  Kazutomo Ori  1 ,  Yuko Aoki  1 ,  Nobuo Shimma  1 ,  Hitoshi Iikura  3
Affiliations
  • 1. Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
  • 2. Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
  • 3. Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan ; Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
PMID: 24900832 DOI: 10.1021/ml400379x
Abstract

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.

Keywords
CH5126766; MEK; Nitrogen scan; RO5126766; Raf; kinase inhibitor.