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Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase
- Source :
- Journal of medicinal chemistry. 63(20)
- Publication Year :
- 2020
-
Abstract
- Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.
- Subjects :
- Epoxide hydrolase 2
Stereochemistry
Neutrophils
01 natural sciences
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Drug Discovery
Structure–activity relationship
Animals
Humans
Lipoxygenase Inhibitors
Cells, Cultured
030304 developmental biology
chemistry.chemical_classification
Epoxide Hydrolases
0303 health sciences
Arachidonate 5-Lipoxygenase
biology
Molecular Structure
Chemistry
Anti-Inflammatory Agents, Non-Steroidal
0104 chemical sciences
Rats
010404 medicinal & biomolecular chemistry
Enzyme
Design synthesis
Drug Design
Arachidonate 5-lipoxygenase
cardiovascular system
biology.protein
Microsomes, Liver
Molecular Medicine
Arachidonic acid
Pharmacophore
Protein Binding
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 63
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....26385089e4d61a587bead1300d2e0028