BIOMAT Database Logo BIOMAT Database Logo

Orally bioavailable potent soluble epoxide hydrolase inhibitors. 2007

Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Department of Entomology and UCD Cancer Center, University of California-Davis, One Shields Avenue, Davis, CA 95616-8584, USA.

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.

UI MeSH Term Description Entries
D007022 Hypotension Abnormally low BLOOD PRESSURE that can result in inadequate blood flow to the brain and other vital organs. Common symptom is DIZZINESS but greater negative impacts on the body occur when there is prolonged depravation of oxygen and nutrients. Blood Pressure, Low,Hypotension, Vascular,Low Blood Pressure,Vascular Hypotension
D008070 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: LIPID A, core polysaccharide, and O-specific chains (O ANTIGENS). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal B-cell mitogens commonly used in laboratory immunology. (From Dorland, 28th ed) Lipopolysaccharide,Lipoglycans
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D002415 Cats The domestic cat, Felis catus, of the carnivore family FELIDAE, comprising over 30 different breeds. The domestic cat is descended primarily from the wild cat of Africa and extreme southwestern Asia. Though probably present in towns in Palestine as long ago as 7000 years, actual domestication occurred in Egypt about 4000 years ago. (From Walker's Mammals of the World, 6th ed, p801) Felis catus,Felis domesticus,Domestic Cats,Felis domestica,Felis sylvestris catus,Cat,Cat, Domestic,Cats, Domestic,Domestic Cat
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D004851 Epoxide Hydrolases Enzymes that catalyze reversibly the formation of an epoxide or arene oxide from a glycol or aromatic diol, respectively. Epoxide Hydrase,Epoxide Hydrases,Epoxide Hydratase,Epoxide Hydratases,Epoxide Hydrolase,9,10-Epoxypalmitic Acid Hydrase,Microsomal Epoxide Hydrolase,Styrene Epoxide Hydrolase,9,10 Epoxypalmitic Acid Hydrase,Acid Hydrase, 9,10-Epoxypalmitic,Epoxide Hydrolase, Microsomal,Epoxide Hydrolase, Styrene,Hydrase, 9,10-Epoxypalmitic Acid,Hydrase, Epoxide,Hydrases, Epoxide,Hydratase, Epoxide,Hydratases, Epoxide,Hydrolase, Epoxide,Hydrolase, Microsomal Epoxide,Hydrolase, Styrene Epoxide,Hydrolases, Epoxide

Related Publications

Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase.
October 2018, Bioorganic chemistry,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators.
October 2018, Scientific reports,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Identification of potent inhibitors of the chicken soluble epoxide hydrolase.
January 2015, Bioorganic & medicinal chemistry letters,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Discovery of potent non-urea inhibitors of soluble epoxide hydrolase.
April 2009, Bioorganic & medicinal chemistry letters,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors.
October 2009, Bioorganic & medicinal chemistry letters,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.
July 2009, Bioorganic & medicinal chemistry letters,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase.
September 2012, Bioorganic & medicinal chemistry letters,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Natural soluble epoxide hydrolase inhibitors from Inula helenium and their interactions with soluble epoxide hydrolase.
April 2020, International journal of biological macromolecules,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Adamantyl thioureas as soluble epoxide hydrolase inhibitors.
July 2018, Bioorganic & medicinal chemistry letters,
Sung Hee Hwang, and Hsing-Ju Tsai, and Jun-Yan Liu, and Christophe Morisseau, and Bruce D Hammock
Soluble epoxide hydrolase inhibitors and cardiovascular diseases.
January 2013, Current vascular pharmacology,
Copied contents to your clipboard!