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

Autor:	Andrew Robertson, Gina Lu, Catherine Sekerke, Bruce A. Steinbaugh, Robert M. Kennedy, Scott D. Larsen, Bruce D. Roth, Mark C. Kowala, Valerie Askew, Bharat K. Trivedi, Kevin Sun, Steve Miller, Yuntao Song, Jeffrey C. Hanselman, Lisa Dillon, William Keun Chan Park, Bradley D. Tait, Bruce Auerbach, Zhiwu Lin
Rok vydání:	2007
Předmět:	Atorvastatin Clinical Biochemistry Pharmaceutical Science Reductase Biochemistry chemistry.chemical_compound Mice In vivo Drug Discovery medicine Animals Combinatorial Chemistry Techniques Rosuvastatin Pyrroles Rosuvastatin Calcium Molecular Biology Muscle Cells Sulfonamides biology Molecular Structure Cholesterol Organic Chemistry nutritional and metabolic diseases Hydroxymethylglutaryl-CoA reductase Fluorobenzenes Disease Models Animal Pyrimidines chemistry Enzyme inhibitor Heptanoic Acids HMG-CoA reductase biology.protein Hepatocytes Molecular Medicine lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.drug
Zdroj:	Bioorganicmedicinal chemistry letters. 18(3)
ISSN:	1464-3405
Popis:	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 Munchnone 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::529bbd001cc056a0d63562fa2b448f60 https://pubmed.ncbi.nlm.nih.gov/18155906 Zobrazit plný text záznamu Full Text from ScienceDirect