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

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.

SUBMITTER: Aoki T

PROVIDER: S-EPMC4027752 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Aoki Toshihiro T Hyohdoh Ikumi I Furuichi Noriyuki N Ozawa Sawako S Watanabe Fumio F Matsushita Masayuki M Sakaitani Masahiro M Morikami Kenji K Takanashi Kenji K Harada Naoki N Tomii Yasushi Y Shiraki Koji K Furumoto Kentaro K Tabo Mitsuyasu M Yoshinari Kiyoshi K Ori Kazutomo K Aoki Yuko Y Shimma Nobuo N Iikura Hitoshi H

ACS medicinal chemistry letters 20140122 4

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 k ...[more]

PMID: 24900832

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