Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors

…, MC Kowala, BK Trivedi, B Auerbach, V Askew…

Index: Park, William K.C.; Kennedy, Robert M.; Larsen, Scott D.; Miller, Steve; Roth, Bruce D.; Song, Yuntao; Steinbaugh, Bruce A.; Sun, Kevin; Tait, Bradley D.; Kowala, Mark C.; Trivedi, Bharat K.; Auerbach, Bruce; Askew, Valerie; Dillon, Lisa; Hanselman, Jeffrey C.; Lin, Zhiwu; Lu, Gina H.; Robertson, Andrew; Sekerke, Catherine Bioorganic and Medicinal Chemistry Letters, 2008 , vol. 18, # 3 p. 1151 - 1156

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Citation Number: 31

Abstract

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 ...