The synthesis of new antilipidemic and antithrombotic aci-reductones of potential use in the treatment of coronary artery disease and related thromboembolic disorders is proposed. This interdisciplinary effort involving medicinal chemists, pharmacologists and lipid biochemists will study structural requirements for selective modification of the anabolism and/or catabolism of serum lipids and apolipoproteins and selected interaction with desirable bioactive membrane targets (platelets, human endothelial cells and vasculature). Antilipidemic activity, liver toxicity and effects on aortic atheromatosis will be assessed in normocholesterolemic, hypercholesterolemic or hypertriglyceridemic rats, rabbits or quail. Changes in total serum cholesterol and triglycerides and individual lipoprotein lipids and apolipoproteins will be measured using spectrophotometric, isoelectric focusing and immunoassay techniques. Active compounds will be studied for their effects on liver lipids, liver microsomal HMG-CoA reductase and cholesterol-7Alpha-hydroxylase activities. Antithrombotic actions, in vitro, will be quantitatively evaluated for their ability to modify platelet activation by stimuli of prostaglandin-dependent and independent pathways in human and rabbit platelet preparations. Ex vivo, antithromobotic effects of promosing compounds will be examined in hyperlipidemic and normal lipemic rabbits. Mechanistic studies of highly promosing analogues are planned to elucidate their effects on platelet phospholipid and prostaglandin metabolism and on formation of prostacyclin in vascular and endothelial tissues. These studies should allow for a delineation of optimal physicochemical properties (configuration, lipophilicity, redox potential), biological selectivity (antilipidemic vs. antithrombotic) and mechanism of action (effects on lipoproteins, apolipoproteins and prostaglandin metabolism) for this chemical class.
