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The in vitro potencies and hypocholesterolemic properties of CL 277,082 and PD 132301-2, two urea inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) were compared. PD 132301-2 was several-fold more potent at inhibiting ACAT in microsomes from rat and rabbit tissues and in cultured cells (murine macrophages and the human HepG2 cell line). This disubstituted urea was also relatively specific for ACAT as other cholesterol esterifying enzymes (e.g., lecithin:cholesterol acyltransferase, pancreatic cholesterol ester hydrolase), as well as intestinal diglyceride synthesis (acyl-CoA:monoglyceride acyltransferase), were unaffected in vitro at relevant concentrations. In normal chow-fed rats, both compounds reduced plasma triglycerides at doses50 mg/kg, but only PD 132301-2 reduced plasma cholesterol. In rat and rabbit models of hypercholesterolemia the greater in vitro potency of PD 132301-2 translated into greater in vivo efficacy (i.e., ED50 values 2- to 3-fold higher for CL 277,082 in both acute and chronic rate models). Of particular note was the greater elevation of high-density lipoprotein-cholesterol and parenteral activity of PD 132301-2 compared to CL 277,082 in the chronic rat model. Inhibition of cholesterol absorption in rats was also greater with PD 132301-2. In guinea pigs, in which 77% of plasma cholesterol was transported in low-density lipoprotein, PD 132301-2 potently reduced plasma total cholesterol (lowest significant dose = 1 mg/kg) as well as plasma triglycerides. CL 277,082 only reduced cholesterol at doses100 mg/kg in this low-density lipoprotein model. In a canine model of hypercholesterolemia CL 277,082 was inactive at doses up to 50 mg/kg, but PD 132301-2 was active at 3 mg/kg. Moreover, efficacy in dogs with PD 132301-2 was positively correlated with plasma drug concentration, an observation not previously demonstrated for other hypolipidemic drugs. The combined data illustrate that pharmacologic activities can vary widely among ACAT inhibitors of the same general class. In addition, the unique observation of proportionality between efficacy and blood drug levels in nonrodent animal models may not only help to simplify early stages in drug development but also may help to predict or monitor a direct action of the drug on vascular disease.