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• W2184834626 abstract "The hypocholesterolemic activity for novel ureido fibrate analogues was found to be over 100-fold greater than for any second-generation fibrate in cholesterol-fed rats. A comparison of 12 related analogues revealed that the optimal configuration for a urea-bridging region located between two aromatic rings consisted of a trisubstituted nitrogen, optimally substituted with a C7 alkyl chain and linked by dimethylene to a phenoxyisobutyrate moiety found in most fibrate analogues. The hypocholesterolemic potency of these compounds was found to correlate with their increased intrinsic fibrate activity as determined by the ability to induce omega-hydroxylase activity either in rat hepatocyte cultures or in vivo, and not with their 10-fold increased ACAT inhibitory potency when compared to other fibrates. The most active compound, 2-(4-(2-(N'-(2,4- difluorophenyl)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2), was found to induce omega-hydroxylase activity in hepatocytes at concentrations between 5 and 100 nM compared to 1-20 microM concentrations for bezafibrate, and lower serum VLDL+LDL cholesterol in rats at doses between 0.1 and 0.5 mg/kg per day compared to doses of 25-100 mg/kg per day for bezafibrate. Single-dose pharmacokinetic studies with 2 indicated that total drug exposure will be much lower at hypocholesterolemic doses due to the enhanced intrinsic activity, and may result in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates." @default.
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• W2184834626 date "1997-06-01" @default.
• W2184834626 modified "2023-10-14" @default.
• W2184834626 title "Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity" @default.
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• W2184834626 doi "https://doi.org/10.1016/s0022-2275(20)37201-1" @default.
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