Abstract
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.
MeSH terms
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Administration, Oral
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Animals
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Imidazoles / administration & dosage
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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MCF-7 Cells
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Male
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Mice
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Mice, Obese
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Molecular Structure
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Piperidines / administration & dosage
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Piperidines / chemistry
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Piperidines / pharmacology*
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Pyrazoles / administration & dosage
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyridines / administration & dosage
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Pyridines / chemistry
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Pyridines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Serine C-Palmitoyltransferase / antagonists & inhibitors*
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Serine C-Palmitoyltransferase / metabolism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Imidazoles
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Piperidines
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Pyrazoles
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Pyridines
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imidazopyridine
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pyrazolopiperidine
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Serine C-Palmitoyltransferase