2013 Dec 20. pii: S0968-0896(13)01017-1. doi: 10.1016/j.bmc.2013.12.023. [Epub ahead of print]
Design, synthesis, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase inhibitors.
Kono M1, Matsumoto T2, Imaeda T2, Kawamura T2, Fujimoto S2, Kosugi Y2, Odani T2, Shimizu Y2, Matsui H2, Shimojo M2, Kori M3.
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.
Copyright © 2013. Published by Elsevier Ltd.
Copyright © 2013. Published by Elsevier Ltd.
KEYWORDS:
2,2,2-trichloroethoxy carbonyl, AEA, Arachidonoylethanolamide, CB1, CB2, CFA, DMPK, EC, FAAH, Fatty acid amide hydrolase inhibitors, Inflammatory pain, Neuropathic pain, PD, PK, Piperazine ureas, SAR, SNI, Structure–activity relationship, Troc, arachidonoylethanolamide, cannabinoid 1, cannabinoid 2, complete Freund’s adjuvant, drug metabolism and pharmacokinetics, endogenous cannabinoid, fatty acid amide hydrolase, pharmacodynamics, pharmacokinetics,sciatic nerve injury
- PMID:
- 24440478
- [PubMed – as supplied by publisher]
