The in vitro and ex vivo antioxidant properties, and hypolipidemic activity of CGP 2881.
This report describes the in vitro and ex vivo antioxidant properties of a new antioxidant, CGP 2881. This compound is structurally similar to probucol, in that both compounds contain bis-tertiary butyl phenyl groups. However, CGP 2881 consistently inhibited CuSO4 (Cu2+)- and macrophage (MO)-induced oxidation of human low density lipoproteins (LDL) more potently than equimolar concentrations of probucol. CGP 2881 (1 mumol/l) prolonged the lag phase of diene formation during Cu(2+)-induced LDL oxidation by 3.4 versus 1.5-fold prolongation with 1 mumol/l probucol (P < 0.05 vs CGP 2881). The IC50 for inhibiting the formation of Cu(2+)-induced thiobarbituric acid-reactive substances (TBARS) was 0.15 mumol/l for CGP 2881, versus approximately 10 mumol/l for probucol. The IC50 for MO-induced oxidation of LDL (TBARS) was 0.64 mumol/l. In contrast, 1 mumol/l probucol failed to inhibit MO-induced oxidation of LDL. Treatment of cholic acid/cholesterol-fed rats with CGP 2881 (50 mg/kg per day, orally for 5 days) inhibited ex vivo Cu(2+)-induced oxidation (TBARS) of the very low density lipoproteins (VLDL) + LDL lipoprotein fraction by 93% versus vehicle controls (P < 0.0001), and prolonged the lag phase for Cu(2+)-induced diene formation by 3.4-fold over vehicle-treated controls. Five days of orally administered CGP 2881 reduced plasma total cholesterol and LDL cholesterol levels to 55 and 54% of vehicle-treated controls, respectively (P < 0.05). In contrast, probucol had no appreciable effect on plasma total cholesterol or LDL cholesterol levels, unless administered for longer than 5 days. Treatment of hypercholesterolemic rabbits with 50 mg/kg per day orally for 5-12 days delayed the lag phase of diene formation during LDL oxidation by 4.3-fold over controls. However, the relative antioxidant potencies of CGP 2881 and probucol seen with oral administration to hypercholesterolemic rabbits were reversed when the compounds were given intravenously. In addition, the effects of these antioxidants were potentiated when given to normocholesterolemic rabbits compared to hypercholesterolemic animals. These data establish that CGP 2881 demonstrates hypolipidemic activity and is a substantially more potent antioxidant than probucol (in vitro and ex vivo). CGP 2881 may be useful as a new antioxidant tool in the effort to better understand the atherogenicity of oxidized LDL (oxLDL).
Metabolic and Cardiovascular Diseases, Pharmaceuticals Division, Novartis Institute for Biomedical Research, NJ 07901, USA. david.feldman@pharma.novartis.com
D L
DL
Feldman
T C
TC
Mogelesky
R
R
Sharif
W K
WK
Sawyer
M
M
Jeune
C W
CW
Hu
K S
KS
Leonards
M F
MF
Prescott
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000097:blood*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D010084:Oxidation-Reduction; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D000975:Antioxidants; C121115:CGP 2881; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D002784:Cholesterol; D011341:Probucol