INHIBITORS OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE .1. SYNTHESIS AND HYPOCHOLESTEROLEMIC ACTIVITY OF DIBENZ[B,E]OXEPIN-11-CARBOXANILIDES

A series of enyl-6,11-dihydrodibenz[b,e]oxepin-11-carboxamides and rel ated derivatives were prepared on the basis of structures of the repor ted inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). These c ompounds were tested for their ability to inhibit ACAT (liver microsom es from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-fed golden hamsters in vivo. The structure- activity relationships in vitro were as follows. Substitution at posit ions 2 and 6 in the anilide resulted in potent inhibitory activity, an d the potency increased with increasing size of the substituents, with maximum potency being obtained with a 2,6-diisopropyl substitution. T he position of the substituent on the dibenz[b,e]oxepin ring system in fluenced the activity, and substitution at position 2 was critical for potent activity. The electronic effect of the substituent at position 2 does not influence activity, but bulkiness seems to be a significan t factor. The lipophilicity of the compounds also plays an important r ole in determining ACAT inhibitory activity. Among the compounds teste d, enyl)-6,11-dihydrodibenz[b,e]oxepin-11-carboxamide (33, KF17828) sh owed significant in vitro activity (rabbit liver microsomes IC50 = 23 nM) and the most potent in vivo activity (complete reduction in elevat ed serum total cholesterol levels at a dose of 10 mg/kg in hamsters).