Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus
| Autor: | Bruce D. Roth, C. J. Blankley, Catherine Sekerke, E. Ferguson, A. W. Chucholowski, Milton L. Hoefle, Roger S. Newton, Charlotte D. Stratton, Daniel F. Ortwine, D. R. Sliskovic |
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| Rok vydání: | 1991 |
| Předmět: |
Magnetic Resonance Spectroscopy
Spectrophotometry Infrared Stereochemistry medicine.drug_class Carboxamide Reductase chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Animals Pyrroles Pyrrole chemistry.chemical_classification biology Molecular Structure Anticholesteremic Agents Rats Enzyme chemistry Liver Pyran Enzyme inhibitor Pyrones biology.protein Molecular Medicine Indicators and Reagents Hydroxymethylglutaryl-CoA Reductase Inhibitors Lactone |
| Zdroj: | Journal of medicinal chemistry. 34(1) |
| ISSN: | 0022-2623 |
| Popis: | A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin. |
| Databáze: | OpenAIRE |
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