DIVERGENT PHARMACOLOGICAL ACTIVITIES OF PD-132301-2 AND CL-277,082, UREA INHIBITORS OF ACYL-COA - CHOLESTEROL ACYLTRANSFERASE

The in vitro potencies and hypocholesterolemic properties of CL 277,08 2 and PD 132301-2, two urea inhibitors of acyl-CoA: cholesterol acyltr ansferase (ACAT) were compared. PD 132301-2 was several-fold more pote nt at inhibiting ACAT in microsomes from rat and rabbit tissues and in cultured cells (murine macrophages and the human HepG2 cell line). Th is disubstituted urea was also relatively specific for ACAT as other c holesterol esterifying enzymes (e.g., lecithin:cholesterol acyltransfe rase, pancreatic cholesterol ester hydrolase), as well as intestinal d iglyceride synthesis (acyl-CoA:monoglyceride acyltransferase), were un affected in vitro at relevant concentrations. In normal chow-fed rats, both compounds reduced plasma triglycerides at doses >50 mg/kg, but o nly PD 132301-2 reduced plasma cholesterol. In rat and rabbit models o f hypercholesterolemia the greater in vitro potency of PD 132301-2 tra nslated 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 parti cular note was the greater elevation of high-density lipoprotein-chole sterol and parenteral activity of PD 132301-2 compared to CL 277,082 i n the chronic rat model. Inhibition of cholesterol absorption in rats was also greater with PD 132301-2. In guinea pigs, in which 77% of pla sma 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 cho lesterol at doses > 100 mg/kg in this low-density lipoprotein model. I n a canine model of hypercholesterolemia CL 277,082 was inactive at do ses up to 50 mg/kg, but PD 132301-2 was active at 3 mg/kg. Moreover, e fficacy in dogs with PD 132301-2 was positively correlated with plasma drug concentration, an observation not previously demonstrated for ot her hypolipidemic drugs. The combined data illustrate that pharmacolog ic activities can vary widely among ACAT inhibitors of the same genera l class. In addition, the unique observation of proportionality betwee n efficacy and blood drug levels in nonrodent animal models may not on ly 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 .