POTENT HYPOCHOLESTEROLEMIC ACTIVITY OF NOVEL UREIDO PHENOXYISOBUTYRATES CORRELATES WITH THEIR INTRINSIC FIBRATE POTENCY AND NOT WITH THEIR ACAT INHIBITORY ACTIVITY

The hypocholesterolemic activity for novel ureido fibrate analogues wa s 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 lo cated between Mo aromatic rings consisted of a trisubstituted nitrogen , optimally substituted with a C-7 alkyl chain and linked by dimethyle ne 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 inhibit ory potency when compared to other fibrates. The most active compound, l)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2),was found to induce omega-hydroxylase activity in hepatocytes a t concentrations between 5 and 100 nM compared to 1-20 mu M concentrat ions for bezafibrate, and lower serum VLDL + LDL cholesterol in rats a t 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 wit h 2 indicated that total drug exposure will be much lower at hypochole sterolemic doses due to the enhanced intrinsic activity, and may resul t in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates.