title: Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Synthesis and hypocholesterolemic activity of dibenz[b,e]oxepin-11-carboxanilides.
abstract: A series of N-phenyl-6,11-dihydrodibenz[b,e]oxepin-11-carboxamides and related derivatives were prepared on the basis of structures of the reported inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). These compounds were tested for their 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 structure-activity relationships in vitro were as follows. Substitution at positions 2 and 6 in the anilide resulted in potent inhibitory activity, and the potency increased with increasing size of the substituents, with maximum potency being obtained with a 2,6-diisopropyl substitution. The position of the substituent on the dibenz[b,e]oxepin ring system influenced 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 significant factor. The lipophilicity of the compounds also plays an important role in determining ACAT inhibitory activity. Among the compounds tested, 2-bromo-N-(2,6-diisopropylphenyl)-6,11-dihydrodibenz-[b,e]++ +oxepin-11- carboxamide (33, KF17828) showed significant in vitro activity (rabbit liver microsomes IC50 = 23 nM) and the most potent in vivo activity (complete reduction in elevated serum total cholesterol levels at a dose of 10 mg/kg in hamsters).
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Limited, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumazawa
authors.forename: M
authors.initials: M
authors.lastname: Yanase
authors.forename: H
authors.initials: H
authors.lastname: Harakawa
authors.forename: H
authors.initials: H
authors.lastname: Obase
authors.forename: S
authors.initials: S
authors.lastname: Shirakura
authors.forename: E
authors.initials: E
authors.lastname: Ohishi
authors.forename: S
authors.initials: S
authors.lastname: Oda
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: K
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D006224:Cricetinae; D003990:Dibenzoxepins / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D002264:Carboxylic Acids; D003990:Dibenzoxepins; C086544:KF 17828; D002785:Sterol O-Acyltransferase