INHIBITION OF CHOLESTEROL ESTER TRANSFER PROTEIN BY CGS-25159 AND CHANGES IN LIPOPROTEINS IN HAMSTERS

As a result of screening, several isoflavans were identified to be ant agonists of cholesterol ester transfer protein (CETP) activity. The pr esent study evaluates CGS 25159, a synthetic isoflavan, as a putative inhibitor of CETP activity of human and hamster plasma. Determined by [H-3]CE transfer from HDL to VLDL + LDL fraction or by fluorescent-CE transfer assay, CGS 25159 inhibited CETP in both human plasma bottom f raction (d = 1.21 g/ml) and in plasma from Golden Syrian Hamsters with an IC50 < 10 mu M. The compound also inhibited (IC50 approximate to 1 5 mu M) the reciprocal transfer of triglycerides in the incubated whol e plasma from normal and hyperlipidemic hamsters. When orally administ ered to normolipidemic hamsters, CGS 25159 (10 mg/kg, 4 days) reduced plasma transfer activity by 35-60%. Treatment with CGS 25159 (10 and 3 0 mg/kg, p.o.) resulted in dose dependent and time dependent changes i n CETP activity. After two weeks of treatment at 10 mg/kg, the changes in VLDL + LDL cholesterol, total triglycerides and HDL cholesterol we re -22 +/- 4.6, -23 +/- 7.5 and +10 +/- 2.8%, respectively. The corre sponding changes at 30 mg/kg were -28 +/- 5.5, -38 +/- 6.8* and +29 /- 4.4%, (*, P, 0.05; mean +/- S.E.M., n = 6). A single spin gradient density ultracentrifugation of plasma lipoproteins from treated anima ls showed an increase in HDL cholesterol and a redistribution to large r HDL particles. These data support the contention that pharmacologica l down regulation of CETP activity could result in favorable changes i n lipoprotein profile. Copyright (C) 1997 Elsevier Science Ireland Ltd .