A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.

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In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.

The glycosphingolipids (GSL) and other major lipid classes were studied in cultured fibroblasts from a family with familial hypercholesterolemia. The GSL content in cells grown in medium containing fetal calf serum was increased 5-fold in the homozygote and 2-to 3-fold in both heterozygous parents. Cell surface labeling experiments, using the membrane probe galactose oxidase followed by reduction with KB3H4, showed an increased incorporation of 3H by the homozygous cells into GL4 (4-fold), GM3 (2-to 3-fold), and GL3a and GD3 (1-to 2-fold); the amount of 3H incorporated by the heterozygous cells was in between that of the homozygous and normal fibroblasts. The specific radioactivity of each of the GSL, except GL2a, was lower in the mutant cells. This unlabeled pool of GSL may be buried in the membrane matrix (less exposure), or located intracellularly, or both. The phospholipids were most markedly elevated (3-fold) in homozygous cells, with a disproportionate increase in phosphatidic acid and sphingomyelin (5-to 6-fold). The content of the GSL, except GL2a, and of the phospholipids was reduced about one-half in the homozygous fibroblasts grown in lipoprotein-deficient medium for 24 hr; by 5 days the GSL content was reduced to only 1.3 times normal and phospholipids to below normal. Incubation of normal fibroblasts in lipoprotein-deficient medium 24 hr had no effect on the GSL or phospholipid content; at 5 days, there was a 50% increase in both GL3a and GL4 with a 25% increase in GM3; there was no change in the phospholipid content. These data suggest that the defective regulation of lipid metabolism in this syndrome may be more extensive than previously realized.Familial hypercholesterolemia (FH) is a disorder of lipid and low-density lipoprotein (LDL) metabolism which is inherited as an autosomal dominant trait and associated with premature atherosclerosis (1, 2). Goldstein and coworkers (3) have demonstrated a lack of functional LDL receptors (receptor-negative) or an alteration in the LDL receptors (receptor-defective) on the cell membrane of cultured fibroblasts from patients with FH. This inability to bind LDL is associated with several abnormalities of lipid and lipoprotein metabolism, which include a lack of feedback inhibition of the rate-limiting enzyme of cholesterol biosynthesis, hydroxymethylglutaryl-CoA reductase (NADPH) [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], decreased conversion of cholesterol to cholesteryl ester, and deficient proteolysis of LDL (4). The mo-

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