Inhibitors of cholesterol biosynthesis. 6. trans-6-[2-(2-N-heteroaryl-3,5-disubstituted-pyrazol-4-yl)ethyl/ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones
| Autor: | J. A. Picard, M. K. Shaw, W. H. Roark, R. L. Stanfield, Roger S. Newton, Bruce David Roth, Drago Robert Sliskovic, B.R. Krause, C. J. Blankley, Catherine Sekerke |
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| Rok vydání: | 1992 |
| Předmět: |
Male
Chemical Phenomena Pyridines Stereochemistry Reductase chemistry.chemical_compound Dogs In vivo Drug Discovery polycyclic compounds medicine Animals Lovastatin Pravastatin Molecular Structure biology Chemistry Physical Chemistry Anticholesteremic Agents nutritional and metabolic diseases Biological activity Hydroxymethylglutaryl-CoA reductase Cholesterol Enzyme inhibitor Pyran Pyrazines biology.protein Pyrazoles Molecular Medicine Female lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 35:2095-2103 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00089a022 |
| Popis: | A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). Two compounds 20a and 20b, were more potent than lovastatin at inhibiting cholesterol biosynthesis both in vitro and in vivo. In terms of plasma cholesterol lowering, 20a was much more efficacious than lovastatin. In addition to possessing increased biological activity, these compounds are significantly less lipophilic than lovastatin, in fact, 20b has a CLOGP value comparable to pravastatin. |
| Databáze: | OpenAIRE |
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