TY - JOUR
T1 - Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties
AU - Huang, Shao Xu
AU - Li, Hui Yuan
AU - Liu, Jun Yan
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Long, Ya Qiu
PY - 2010/12/9
Y1 - 2010/12/9
N2 - 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 N4-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: T 1/2 =14 h, Cmax = 84 nM, AUC = 40 200 nM·min, and IC50 = 7.0 nM against human sEH enzyme.
AB - 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 N4-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: T 1/2 =14 h, Cmax = 84 nM, AUC = 40 200 nM·min, and IC50 = 7.0 nM against human sEH enzyme.
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U2 - 10.1021/jm101087u
DO - 10.1021/jm101087u
M3 - Article
C2 - 21070033
AN - SCOPUS:78649806238
VL - 53
SP - 8376
EP - 8386
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -