期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 1, 页码 61-81出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01239
关键词
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资金
- Else-Kroner-Fresenius Foundation graduate college for Translational Research Innovation - Pharma (TRIP)
- Deutsche Forschungsgemeinschaft (DFG) [Sachbeihilfe PR1405/1-2, SFB 1039 Teilprojekte A02, SFB 1039 Teilprojekte A07, SFB 1039 Teilprojekte Z01]
- graduate college for Translational Research Innovation - Pharma (TRIP)
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 gamma (PPAR gamma). Simultaneous modulation of sEH and PPAR gamma can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPAR gamma pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 mu M/PPAR gamma EC50 = 0.3 mu M) 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.
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