INHIBITORS OF ACYL-COA - CHOLESTEROL ACYLTRANSFERASE .2. PREPARATION AND HYPOCHOLESTEROLEMIC ACTIVITY OF OPTICALLY-ACTIVE DIBENZ[B,E]OXEPIN-11-CARBOXANILIDES

In a previous paper, we reported a novel inhibitor of acyl-CoA: choles terol acyltransferase (ACAT), enyl)-6,11-dihydrodibenz[b,e]oxepin-11-c arboxamide (1). In this work, we prepared both enantiomers and tested them for ability to inhibit ACAT (Liver microsomes from cholesterol-fe d rabbits) in vitro and to decrease serum total cholesterol in cholest erol-fed golden hamsters in vivo, The precursor carboxylic acid 4 was optically resolved with cinchonidine. The obtained (-)- and (+)-4 were converted to (-)- and(+)-1 without racemization, respectively, The en antiomer (-)-1 showed potent ACAT inhibitory activity in vitro with an IC50 value of 8 nM and was approximately 10-fold more active than (+) -1, Furthermore, (-)-1 showed strong hypocholesterolemic activity in v ivo, whereas (+)-1 was inactive. A molecular modeling study showed tha t the difference of ACAT inhibitory activity between the enantiomers w as derived from the spatial alignment of the bromine. Compound (-)-1 w as selected for further evaluation as KW-3033.