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

被引：31

作者：

Hyohdoh, Ikumi ^{[1
]}

Furuichi, Noriyuki ^{[1
]}

Aoki, Toshihiro ^{[1
]}

Itezono, Yoshiko ^{[1
]}

Shirai, Haruyoshi ^{[1
]}

Ozawa, Sawako ^{[1
]}

Watanabe, Fumio ^{[1
]}

Matsushita, Masayuki ^{[1
]}

Sakaitani, Masahiro ^{[1
]}

Ho, Pil-Su ^{[3
]}

Takanashi, Kenji ^{[1
]}

Harada, Naoki ^{[1
]}

Tomii, Yasushi ^{[1
]}

Yoshinari, Kiyoshi ^{[1
]}

Ori, Kazutomo ^{[1
]}

Tabo, Mitsuyasu ^{[2
]}

Aoki, Yuko ^{[1
]}

Shimma, Nobuo ^{[1
]}

Iikura, Hitoshi ^{[1
,2
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Div Res, Kamakura, Kanagawa 2478530, Japan

[2] Chugai Pharmaceut Co Ltd, Div Res, Shizuoka 4128513, Japan

[3] Sungkyunkwan Univ, C&C Res Labs, Suwon 440746, Gyeonggi Do, South Korea

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 11期

关键词：

Fluorine scan; Raf; MEK; kinase inhibitor; anticancer; C-F; TRIFLUOROMETHYLATION; CHEMISTRY; THROMBIN;

D O I：

10.1021/ml4002419

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 la 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 la 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.

引用

页码：1059 / 1063

页数：5

共 22 条

[1] Electrophilic fluorination with N,N′-difluoro-2,2′-bipyridinium salt and elemental fluorine [J].

Adachi, K ;

Ohira, Y ;

Tomizawa, G ;

Ishihara, S ;

Oishi, S .

JOURNAL OF FLUORINE CHEMISTRY, 2003, 120 (02) :173-183

[2]

Aoki T., 2013, BIOORG MED CHE UNPUB

[3] Fluorine in medicinal chemistry [J].

Böhm, HJ ;

Banner, D ;

Bendels, S ;

Kansy, M ;

Kuhn, B ;

Müller, K ;

Obst-Sander, U ;

Stahl, M .

CHEMBIOCHEM, 2004, 5 (05) :637-643

[4] Solvent effect on intramolecular hydrogen bonds in push-pull conjugated molecules [J].

Bouchy, A ;

Rinaldi, D ;

Rivail, JL .

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, 2004, 96 (03) :273-281

[5] The many roles for fluorine in medicinal chemistry [J].

Hagmann, William K. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (15) :4359-4369

[6]

Iikura H., 2011, P AM ASSOC CANC RES

[7] Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity [J].

Ishii, Nobuya ;

Harada, Naoki ;

Joseph, Eric W. ;

Ohara, Kazuhiro ;

Miura, Takaaki ;

Sakamoto, Hiroshi ;

Matsuda, Yutaka ;

Tomii, Yasushi ;

Tachibana-Kondo, Yukako ;

Iikura, Hitoshi ;

Aoki, Toshihiro ;

Shimma, Nobuo ;

Arisawa, Mikio ;

Sowa, Yoshihiro ;

Poulikakos, Poulikos I. ;

Rosen, Neal ;

Aoki, Yuko ;

Sakai, Toshiyuki .

CANCER RESEARCH, 2013, 73 (13) :4050-4060

[8] Fluorination in medicinal chemistry: Methods, strategies, and recent developments [J].

Kirk, Kenneth L. .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2008, 12 (02) :305-321

[9]

Kirsch P., 2013, Modern Fluoroorganic Chemistry

[10] Recent Advances in Catalytic Enantioselective Fluorination Reactions [J].

Lectard, Sylvain ;

Hamashima, Yoshitaka ;

Sodeoka, Mikiko .

ADVANCED SYNTHESIS & CATALYSIS, 2010, 352 (16) :2708-2732

← 1 2 3 →