Inhibitors of Acyl-CoA : Cholesterol Acyltransferase. II. 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 : cholesterol acyltransferase (ACAT), 2-bromo-N-(2, 6-diisopropylphenyl)-6, 11-dihydrodibenz[b, e]oxepin-11-carboxamide (1). In this work, we prepared both enantiomers and tested them for ability to inhibit ACAT (liver microsomes from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-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 enantiomer (-)-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 vivo, whereas (+)-1 was inactive.A molecular modeling study showed that the difference of ACAT inhibitory activity between the enantiomers was derived from the spatial alignment of the bromine.Compound (-)-1 was selected for further evaluation as KW-3033.