Hepatoselectivity of statins: Design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors
Bioorganic & Medicinal Chemistry Letters(2008)
摘要
4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.
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关键词
LDL-C,HMG-CoA reductase,Atorvastatin,Rosuvastatin,Organic anion transporting polypeptides,Hydrophilicity,Lipophilicity,ClogP,L6-myocytes,Hepatocytes
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