Influence of membrane partitioning on inhibitors of membrane-bound enzymes.

Membrane-water partitioning of inhibitors of acyl-coenzyme A:cholesterol acyltransferase (ACAT) governs the concentration of inhibitor that ACAT is exposed to and determines the corresponding extent of cholesterol esterification inhibition. Partitioning of the ACAT inhibitors CI-976, CL 277,082, and SaH 58-035 into rat liver microsomes containing ACAT was detected by shifts in the level of inhibition that were independent of inhibitor concentration but inversely dependent on microsome membrane concentration. The equilibrium distribution of the ACAT inhibitors between aqueous and membrane phases was derived directly from these data by application of a previously described method of linear analysis.

Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates.

Sulfoacetic acid, phosphoramidate, and phosphoramide analogs of the ACAT inhibitors, CI-999 and CI-1011 were synthesized. The structure-activity relationships of these compounds as ACAT inhibitors are described.

Phospholipase A2 relieves phosphatidylcholine inhibition of micellar cholesterol absorption and transport by human intestinal cell line Caco-2.

Cholesterol absorption from bile acid micelles is suppressed by phosphatidylcholine (PC) in the micelles. The effects of micellar phospholipid composition on absorption, metabolism, and secretion of lipids were examined in Caco-2 cells incubated with micelles composed of taurocholic acid, cholesterol, oleic acid, monooleoylglycerol, and phospholipid. Significant amounts of all micelle lipids were absorbed from micelles lacking phospholipid.

alpha-Substituted malonester amides: tools to define the relationship between ACAT inhibition and adrenal toxicity.

We prepared a series of alpha-substituted malonester amides that were evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase activity in vitro and to lower plasma total cholesterol levels in a variety of cholesterol-fed animal models. Compounds of this series were also useful in examining the relationship between adrenal toxicity and ACAT inhibition. One compound from this series, 9f, was a potent inhibitor of ACAT in both the microsomal and cellular assays.

Inhibitors of acyl-CoA:cholesterol acyltransferase: novel trisubstituted ureas as hypocholesterolemic agents.

Our continued interest in developing novel, potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, and our discovery of several active series of disubstituted urea ACAT inhibitors, have led us to investigate a series of trisubstituted ureas that are structural hybrids of our disubstituted series and of a trisubstituted urea ACAT inhibitor series disclosed by scientists at Lederle. This investigation has led to the discovery of novel trisubstituted ureas, several of which inhibit ACAT in the nanomolar range and effectively lower total plasma cholesterol when administered as a diet admixture in an acute model of hypercholesterolemia in rats. One analogue (35) also lowered total cholesterol as efficaciously as CL 277,082 in our chronic hypercholesterolemic rat model.