HETEROCYCLIC AMIDES - INHIBITORS OF ACYL-COA-CHOLESTEROL O-ACYL TRANSFERASE WITH HYPOCHOLESTEROLEMIC ACTIVITY IN SEVERAL SPECIES AND ANTIATHEROSCLEROTIC ACTIVITY IN THE RABBIT

A series of heterocyclic amides were synthesized and evaluated as inhi bitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evalu ated for cell-based macrophage ACAT inhibition, bioactivity, and adren al toxicity. Candidates were selected for evaluation in cholesterol-fe d dogs and, ultimately, the injured cholesterol-fed rabbit model of at herosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 mu M), and the majority of compounds signif icantly towered plasma cholesterol (42-68%) in an acute cholesterol-fe d rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a c ell-based macrophage ACAT assay. Two highly bioactive analogs, 5-yl)-2 -phenyl-N-(2,4,6-trimethoxyphenyl)acetamide (13a) and 3-yl)-2-phenyl-N -(2,4,6-trimethoxyphenyl)acetamide (16a), were selected for further st udy and were found to be nontoxic in a guinea pig model of adrenal tox icity. Compounds 13a and 16a lowered total cholesterol in the choleste rol-fed rat, rabbit, and dog models of pre-established hypercholestero lemia. Compound 13a in the injured cholesterol-fed rabbit model of ath erosclerosis was effective in slowing the development of cholesteryl e ster-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.