Work

Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

Year: 2007

Type: article

Abstract: A series of N,N'-disubstituted ureas having a conformationally restricted cis- or trans-1,4-cyclohexane alpha to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC50 = 1.3 +/- 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/jm070270t

Authors: Sung Hee Hwang, Hsing-Ju Tsai, Jun-Yan Liu, Christophe Morisseau, Bruce D. Hammock

Institutions: UC Davis Comprehensive Cancer Center, University of California, Davis

Language: English

Topic: Eicosanoids and Hypertension Pharmacology

Subfield: Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Department of Higher Education and Training, National Institute of Environmental Health Sciences