Inhibitors of Acyl-CoA : Cholesterol Acyltransferase. II. Preparation and Hypocholesterolemic Activity of Optically Active Dibenz[b, e]oxepin-11-carboxanilides

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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 IC_<50> 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.
公益社団法人日本薬学会の論文
1996-01-15