rosuvastatin and Disease-Models--Animal

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.

Topics: Animals; Atorvastatin; Combinatorial Chemistry Techniques; Disease Models, Animal; Fluorobenzenes; Hepatocytes; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Molecular Structure; Muscle Cells; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Sulfonamides