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

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• 作者：Mitsunori Kono ; Takahiro Matsumoto ; Toshihiro Imaeda ; Toru Kawamura ; Shinji Fujimoto ; Yohei Kosugi ; Tomoyuki Odani ; Yuji Shimizu ; Hideki Matsui ; Masato Shimojo ; Masakuni Kori
• 关键词：FAAH ; fatty acid amide hydrolase ; EC ; endogenous cannabinoid ; AEA ; arachidonoylethanolamide ; CB1 ; cannabinoid 1 ; CB2 ; cannabinoid 2 ; SAR ; Structure&ndash ; activity relationship ; DMPK ; drug metabolism and pharmacokinetics ; PK ; pharmacokinetics ; PD ; pharmacodynamics ; Troc ; 2 ; 2 ; 2-trichloroethoxy carbonyl ; CFA ; complete Freund&rsquo ; s adjuvant ; SNI ; sciatic nerve injury
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 February, 2014
• 年：2014
• 卷：22
• 期：4
• 页码：1468-1478
• 全文大小：1389 K

文摘

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.