title: Inhibitors of acyl-CoA: cholesterol acyltransferase. II. Preparation and hypocholesterolemic activity of optically active dibenz[b,e]oxepin-11-carboxanilides.
abstract: 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.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumazawa
authors.forename: M
authors.initials: M
authors.lastname: Yanase
authors.forename: S
authors.initials: S
authors.lastname: Shirakura
authors.forename: E
authors.initials: E
authors.lastname: Ohishi
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Matsumiya
authors.forename: M
authors.initials: M
authors.lastname: Kono
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D003990:Dibenzoxepins / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008647:Mesocricetus; D011817:Rabbits; D013237:Stereoisomerism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000924:Anticholesteremic Agents; D003990:Dibenzoxepins; D004791:Enzyme Inhibitors; C086544:KF 17828; D002784:Cholesterol; D002785:Sterol O-Acyltransferase