The Clinical Pharmacology of SQ 31,000 (CS 514) in Healthy Subjects

Atherosclerosis, with the attendant consequences of coronary heart disease and stroke, is the major cause of death in the United States and most developed countries. Elevated serum cholesterol and, in particular, the low-density lipoprotein (LDL) fraction is a major risk factor in the development of arteriosclerotic disease in both animals and humans (Consensus Conference 1985, AHA Special Report 1984). Currently available lipid-lowering drugs are either poorly tolerated, cumbersome to ingest, or lack substantial effect on cholesterol or LDL. SQ 31,000: (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S, 8S, 8aR)-1,2,6,7,8,8a-hexahydro-6-hydroxy-2-methyl-8-[(S)-2-methyl-l-oxobutoxy]-1-naphthalenyl]-heptanoic acid, monosodium salt (Fig. 1), is a new HMG-CoA reductase inhibitor, structurally related to lovastatin and compactin. These agents are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Both lovastatin and compactin have been reported to lower total cholesterol and LDL in healthy volunteers (Tobert et al. 1982) and in patients with familial hypercholesterolemia (Mabuchi et al. 1983; Illingworth and Sexton 1984). The cholesterol-lowering effects of these inhibitors are believed to be due to modest reductions in cellular pools of cholesterol, resulting in compensatory increases in the number of LDL receptors and enhanced clearance of cholesterol from the circulation (Bilheimer et al. 1983; Grundy and Bilheimer 1983). SQ 31,000 has been shown to be equipotent to lovastatin and compactin but is a more tissue-specific inhibitor of sterol synthesis (Tsujita et al. 1986).