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

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 se...

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Published in:Bioorganic & medicinal chemistry 2008-02, Vol.18 (3), p.1151-1156
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Atorvastatin
Atorvastatin Calcium
Biological and medical sciences
C log P
Combinatorial Chemistry Techniques
Disease Models, Animal
Fluorobenzenes - pharmacology
General and cellular metabolism. Vitamins
Hepatocytes
Hepatocytes - drug effects
Heptanoic Acids - pharmacology
HMG-CoA reductase
Hydrophilicity
Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemical synthesis
Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
L6-myocytes
LDL-C
Lipophilicity
Medical sciences
Mice
Molecular Structure
Muscle Cells - drug effects
Organic anion transporting polypeptides
Pharmacology. Drug treatments
Pyrimidines - pharmacology
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
Rosuvastatin
Rosuvastatin Calcium
Sulfonamides - chemical synthesis
Sulfonamides - pharmacology
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Summary: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 C log P 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.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2007.11.124