2. Academic Validation
  3. Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

  • ACS Med Chem Lett. 2013 Sep 22;4(11):1059-63. doi: 10.1021/ml4002419.
Ikumi Hyohdoh 1,  Noriyuki Furuichi 1,  Toshihiro Aoki 1,  Yoshiko Itezono 1,  Haruyoshi Shirai 1,  Sawako Ozawa 1,  Fumio Watanabe 1,  Masayuki Matsushita 1,  Masahiro Sakaitani 1,  Pil-Su Ho 2,  Kenji Takanashi 1,  Naoki Harada 1,  Yasushi Tomii 1,  Kiyoshi Yoshinari 1,  Kazutomo Ori 1,  Mitsuyasu Tabo 3,  Yuko Aoki 1,  Nobuo Shimma 1,  Hitoshi Iikura 4
Affiliations

Affiliations

  • 1 Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
  • 2 C&C Research Laboratories, DRC Natural Sciences Campus, Sungkyunkwan University , 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Republic of Korea.
  • 3 Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
  • 4 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: 24900605 DOI: 10.1021/ml4002419
Abstract

A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.

Keywords

Fluorine scan; MEK; Raf; anticancer; kinase inhibitor.

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