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

ABSTRACT: The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation and other cardiovascular disorders. 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.

SUBMITTER: Huang SX

PROVIDER: S-EPMC4163146 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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

Huang Shao-Xu SX Cao Bin B Morisseau Christophe C Jin Yi Y Hammock Bruce D BD Long Ya-Qiu YQ

MedChemComm 20120301 3

The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation and other cardiovascular disorders. 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 ...[more]

PMID: 25225606

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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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