Abstract
A series of carnitine related compounds of general formula XCH(2)CHZRCH(2)Y were evaluated as CPT I inhibitors in intact rat liver (L-CPT I) and heart mitochondria (M-CPT I). Derivative 27 (ZR = -HNSO(2)R, R = C(12), X = trimethylammonium, Y = carboxylate, (R) form) showed the highest activity (IC(50) = 0.7 microM) along with a good selectivity (M-CPT I/L-CPTI IC(50) ratio = 4.86). Diabetic db/db mice treated orally with 27 showed a significant reduction of serum glucose levels.
MeSH terms
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3-Hydroxybutyric Acid / blood
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Animals
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Carnitine / analogs & derivatives*
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Carnitine / chemical synthesis*
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Carnitine / chemistry
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Carnitine / pharmacology
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Carnitine O-Palmitoyltransferase / antagonists & inhibitors*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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In Vitro Techniques
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Mitochondria, Heart / drug effects
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Mitochondria, Heart / metabolism
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Mitochondria, Liver / drug effects
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Mitochondria, Liver / metabolism
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Hypoglycemic Agents
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Carnitine O-Palmitoyltransferase
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Carnitine
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3-Hydroxybutyric Acid