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N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators
- Source :
- Journal of Medicinal Chemistry. 59:61-81
- Publication Year :
- 2015
- Publisher :
- American Chemical Society (ACS), 2015.
-
Abstract
- Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 μM/PPARγ EC50 = 0.3 μM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.
- Subjects :
- 0301 basic medicine
Epoxide hydrolase 2
Administration, Oral
Peroxisome proliferator-activated receptor
In Vitro Techniques
Pharmacology
Mice
Structure-Activity Relationship
03 medical and health sciences
In vivo
Chlorocebus aethiops
Drug Discovery
Animals
Humans
Structure–activity relationship
Enzyme Inhibitors
IC50
ADME
Epoxide Hydrolases
Metabolic Syndrome
chemistry.chemical_classification
Chemistry
3T3 Cells
Rats
PPAR gamma
030104 developmental biology
Diabetes Mellitus, Type 2
Drug Design
Benzamides
COS Cells
Hypertension
Microsomes, Liver
Molecular Medicine
Drug Screening Assays, Antitumor
Pharmacophore
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....3ae556f64565e7402baab643884a823e