Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents
Autor: | Ann Holmes, Bruce D. Roth, C. J. Blankley, Essenburg Ad, K.A. Kieft, W. H. Roark, R. L. Stanfield, Bharat K. Trivedi, Brian R. Krause, Milton L. Hoefle |
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Rok vydání: | 1992 |
Předmět: |
Male
medicine.drug_class Sterol O-acyltransferase Alpha (ethology) Carboxamide Cholesterol Dietary Structure-Activity Relationship In vivo Drug Discovery medicine Animals Potency IC50 Hypolipidemic Agents chemistry.chemical_classification Fatty acid Rats Inbred Strains Rats Cholesterol Enzyme chemistry Biochemistry Molecular Medicine lipids (amino acids peptides and proteins) Rabbits Sterol O-Acyltransferase |
Zdroj: | Journal of Medicinal Chemistry. 35:1609-1617 |
ISSN: | 1520-4804 0022-2623 |
DOI: | 10.1021/jm00087a016 |
Popis: | A series of fatty acid anilides was prepared, and compounds were tested for their ability to inhibit the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and to lower plasma total cholesterol and elevate high-density lipoprotein cholesterol in cholesterol-fed rats in vivo. The compounds reported were found to fall into two subclasses with different anilide SAR. For nonbranched acyl analogues, inhibitory potency was found to be optimal with bulky 2,6-dialkyl substitution. For alpha-substituted acyl analogues, there was little dependence of in vitro potency on anilide substitution and 2,4,6-trimethoxy was uniquely preferred. Most of the potent inhibitors (IC50 less than 50 nM) were found to produce significant reductions in plasma total cholesterol in cholesterol-fed rats. Additionally, in vivo activity could be improved significantly by the introduction of alpha,alpha-disubstitution into the fatty acid portion of the molecule. A narrow group of alpha,alpha-disubstituted trimethoxyanilides, exemplified by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (39), was found to not only lower plasma total cholesterol (-60%) in cholesterol-fed rats but also elevate levels of high-density lipoprotein cholesterol (+94%) in this model at the screening dose of 0.05% in the diet (ca. 50 mg/kg). |
Databáze: | OpenAIRE |
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