Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach.

Kosuke Anan, Moriyasu Masui, Shinichiro Hara, Miho Ohara, Masaharu Kume, Shoichi Yamamoto, Shunji Shinohara, Hiroki Tsuji, Shinji Shimada, Shigenori Yagi, Nobuyoshi Hasebe, Hiroyuki Kai

Bioorganic & medicinal chemistry letters 2017 Sep 01

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NR2B subunit containing N-methyl-d-aspartate (NMDA) receptor is an attractive target for chronic pain due to its involvement in disease states and its limited distribution in the central nervous system. Cyclohexanol-based leads 6a and 6c were identified as potent NR2B-selective NMDA antagonists utilizing a scaffold hopping approach. Further optimization of this series through replacement of the amide in the leads with an isoxazole and efforts to optimize the pharmacokinetic profiles led to the discovery of orally available brain penetrants 7k and 7l, which demonstrated analgesic activity in the mouse formalin test at early and late phases. Copyright © 2017. Published by Elsevier Ltd.

Citation

Kosuke Anan, Moriyasu Masui, Shinichiro Hara, Miho Ohara, Masaharu Kume, Shoichi Yamamoto, Shunji Shinohara, Hiroki Tsuji, Shinji Shimada, Shigenori Yagi, Nobuyoshi Hasebe, Hiroyuki Kai. Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach. Bioorganic & medicinal chemistry letters. 2017 Sep 01;27(17):4194-4198