Issue 3, 2012
From the journal:

MedChemComm

Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase

Shao-Xu Huang,a   Bin Cao,a   Christophe Morisseau,b   Yi Jin,c   Bruce D. Hammockb  and  Ya-Qiu Long*a  

* Corresponding authors

a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, China
E-mail: yqlong@mail.shcnc.ac.cn
Fax: +86-21-50806876
Tel: +86-21-50806876

b Department of Entomology and University of California Davis Cancer Center, University of California, One Shields Avenue, Davis, CA, USA

c School of Chemical Science and Technology, Yunnan University, Kunming, China

Abstract

The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of cardiovascular, inflammation and other disorders. A piperazino functionality as the tertiary pharmacophore remarkably improved the drug-like profile of the 1,3-disubstituted urea sEH inhibitors. However, the potency was more dependent on the overall best balance of the hydrophilicity and lipophilicity. Based on the sEH-inhibitor complex structure, further structural optimization on the piperazino-containing 1,3-disubstituted urea scaffold was conducted for an improved potency. The 1-adamantylacetamide and para-phenylcarbonyl group were identified to be an optimal primary pharmacophore and secondary pharmacophore motif, respectively, generating sub-nanomolar sEH inhibitors with favorable water solubility.

Graphical abstract: Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase

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Article information

DOI
https://doi.org/10.1039/C2MD00288D
Article type
Concise Article
Submitted
17 Nov 2011
Accepted
22 Dec 2011
First published
05 Jan 2012

Med. Chem. Commun., 2012,3, 379-384

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Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase

S. Huang, B. Cao, C. Morisseau, Y. Jin, B. D. Hammock and Y. Long, Med. Chem. Commun., 2012, 3, 379 DOI: 10.1039/C2MD00288D

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