Abstract
Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure-activity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / analysis
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CHO Cells
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Cricetinae
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Cricetulus
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Eating / drug effects
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Hepatocytes / metabolism
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Male
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Membranes, Artificial
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Mice
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Mice, Obese
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Permeability
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology
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Solubility
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Sterol Regulatory Element Binding Proteins / antagonists & inhibitors*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Blood Glucose
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Membranes, Artificial
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N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide
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Pyridines
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Sterol Regulatory Element Binding Proteins
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Sulfonamides
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Thiazoles
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fatostatin