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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 [J Med Chem] 2016 Jan 14; Vol. 59 (1), pp. 61-81. Date of Electronic Publication: 2015 Dec 25. - Publication Year :
- 2016
-
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 :
- 3T3 Cells
Administration, Oral
Animals
Benzamides pharmacokinetics
COS Cells
Chlorocebus aethiops
Diabetes Mellitus, Type 2 drug therapy
Drug Design
Drug Screening Assays, Antitumor
Enzyme Inhibitors pharmacokinetics
Humans
Hypertension drug therapy
In Vitro Techniques
Mice
Microsomes, Liver metabolism
Rats
Structure-Activity Relationship
Benzamides chemical synthesis
Benzamides pharmacology
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacology
Epoxide Hydrolases antagonists & inhibitors
Metabolic Syndrome drug therapy
PPAR gamma drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 59
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26595749
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b01239