2. Academic Validation
  3. Design, synthesis, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase inhibitors

Design, synthesis, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase inhibitors

  • Bioorg Med Chem. 2014 Feb 15;22(4):1468-78. doi: 10.1016/j.bmc.2013.12.023.
Mitsunori Kono 1,  Takahiro Matsumoto 2,  Toshihiro Imaeda 2,  Toru Kawamura 2,  Shinji Fujimoto 2,  Yohei Kosugi 2,  Tomoyuki Odani 2,  Yuji Shimizu 2,  Hideki Matsui 2,  Masato Shimojo 2,  Masakuni Kori 3
Affiliations

Affiliations

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: mitsunori.kouno@takeda.com.
  • 2 Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 CMC Center, Takeda Pharmaceutical Company Ltd, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan.
PMID: 24440478 DOI: 10.1016/j.bmc.2013.12.023
Abstract

A series of piperazine ureas were designed, synthesized, and evaluated for their potential as novel orally efficacious fatty acid amide hydrolase (FAAH) inhibitors for the treatment of neuropathic and inflammatory pain. We carried out an optimization study of compound 5 to improve its in vitro FAAH inhibitory activity, and identified the 2-pyrimidinylpiperazine derivative 21d with potent inhibitory activity, favorable DMPK profile and brain permeability. Compound 21d showed robust and dose-dependent analgesic efficacy in animal models of both neuropathic and inflammatory pain.

Keywords

Arachidonoylethanolamide; Fatty acid amide hydrolase inhibitors; Inflammatory pain; Neuropathic pain; Piperazine ureas.

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