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J Med Chem. 2010 Dec 9;53(23):8376-86. doi: 10.1021/jm101087u. Epub 2010 Nov 11.

Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties.

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1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Abstract

The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation, and other disorders. However, the problems of limited water solubility, high melting point, and low metabolic stability complicated the development of 1,3-disubstituted urea-based sEH inhibitors. The current study explored the introduction of the substituted piperazino group as the tertiary pharmacophore, which resulted in substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors while retaining high potency. The SAR studies revealed that the meta- or para-substituted phenyl spacer and N(4)-acetyl or sulfonyl substituted piperazine were optimal structures for achieving high potency and good physical properties. The 1-(4-(4-(4-acetylpiperazin-1-yl)butoxy)phenyl)-3-adamantan-1-yl urea (29c) demonstrated excellent in vivo pharmacokinetic properties in mice: T1/2 =14 h, Cmax = 84 nM, AUC = 40 200 nM·min, and IC50 = 7.0 nM against human sEH enzyme.

PMID:
21070033
PMCID:
PMC3070159
DOI:
10.1021/jm101087u
[Indexed for MEDLINE]
Free PMC Article
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