title: Synthesis and structure-activity studies of novel orally active non-terpenoic 2,3-oxidosqualene cyclase inhibitors.
abstract: New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.
authors.affiliation: Pharmaceuticals Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Dehmlow
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Aebi
authors.forename: Synèse
authors.initials: S
authors.lastname: Jolidon
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Ji
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: von der Mark
authors.forename: Jacques
authors.initials: J
authors.lastname: Himber
authors.forename: Olivier H
authors.initials: OH
authors.lastname: Morand
mesh_terms: D000284:Administration, Oral; D000499:Allylamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000201:enzymology; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D006224:Cricetinae; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D001577:Benzophenones; D008078:Cholesterol, LDL; D013844:Thiazoles; C476443:allyl(6-(3-(4-bromophenyl)benzo(d)isothiazol-6-yloxy)hexyl)methylamine; C105726:Ro 48-8071; D000499:Allylamine; D002784:Cholesterol; D019751:Intramolecular Transferases; C021923:cycloartenol synthase