Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents
| العنوان: | Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents |
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| المؤلفون: | 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 |
| المصدر: | Journal of Medicinal Chemistry. 35:1609-1617 |
| بيانات النشر: | American Chemical Society (ACS), 1992. |
| سنة النشر: | 1992 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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). |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b6e850c63582d3658c596051af28b574 https://doi.org/10.1021/jm00087a016 |
| رقم الأكسشن: | edsair.doi.dedup.....b6e850c63582d3658c596051af28b574 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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