A series of fatty acid anilides was prepared, and compounds were tested for their ability to inhibit the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and to lower plasma total cholesterol and elevate high-density lipoprotein cholesterol in cholesterol-fed rats in vivo. The compounds reported were found to fall into two subclasses with different anilide SAR. For nonbranched acyl analogues, inhibitory potency was found to be optimal with bulky 2,6-dialkyl substitution. For alpha-substituted acyl analogues, there was little dependence of in vitro potency on anilide substitution and 2,4,6-trimethoxy was uniquely preferred. Most of the potent inhibitors (IC50 less than 50 nM) were found to produce significant reductions in plasma total cholesterol in cholesterol-fed rats. Additionally, in vivo activity could be improved significantly by the introduction of alpha,alpha-disubstitution into the fatty acid portion of the molecule. A narrow group of alpha,alpha-disubstituted trimethoxyanilides, exemplified by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (39), was found to not only lower plasma total cholesterol (-60%) in cholesterol-fed rats but also elevate levels of high-density lipoprotein cholesterol (+94%) in this model at the screening dose of 0.05% in the diet (ca. 50 mg/kg).

The synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.

A series of 1,3,5-trisubstituted pyrazole mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Since previous studies suggested that the 5-(4-fluorophenyl) and 3-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations in position 1 of the pyrazole ring. Biological evaluation of analogues bearing a variety of 1-substituents suggested that, although most substituents were tolerated, none afforded an advantage over phenyl, which exhibited potency comparable to that of compactin in vitro.