Abe Hiroyuki, Kikuchi Shinichi, Hayakawa Kazuhide, Iida Tetsuya, Nagahashi Noboru, Maeda Katsuya, Sakamoto Johei, Matsumoto Noriaki, Miura Tomoya, Matsumura Koji, Seki Noriyoshi, Inaba Takashi, Kawasaki Hisashi, Yamaguchi Takayuki, Kakefuda Reina, Nanayama Toyomichi, Kurachi Hironori, Hori Yoshikazu, Yoshida Takayuki, Kakegawa Junya, Watanabe Yoshihiro, Gilmartin Aidan G, Richter Mark C, Moss Katherine G, Laquerre Sylvie G
Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Pharmaceutical Frontier Research Laboratory, Japan Tobacco, 1-13-2 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
ACS Med Chem Lett. 2011 Feb 28;2(4):320-4. doi: 10.1021/ml200004g. eCollection 2011 Apr 14.
Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.
抑制丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）是发现新一代抗癌化疗药物的一种有前景的策略。我们从先导化合物2开始进行合成研究，旨在提高对癌细胞的抗增殖活性以及改善各种药物性质。这些研究工作促成了N-{3-[3-环丙基-5-(2-氟-4-碘苯氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜溶剂化物（GSK1120212，JTP-74057 DMSO溶剂化物；1）的发现，它是一种具有改善药物性质的选择性且高效的MEK抑制剂。我们进一步证实了抗增殖活性与细胞MEK抑制相关，并在肿瘤异种移植模型中观察到每日口服1具有显著的抗肿瘤活性。这些特性使得1被选用于临床开发。
