title: Discovery of atrop fixed alkoxy-aminobenzhydrol derivatives: novel, highly potent and orally efficacious squalene synthase inhibitors.
abstract: We have recently reported the discovery of the new benzhydrol template, which has a highly potent inhibitory activity for squalene synthase, as typified by compound 1 (SSI IC(50)=0.85 nM). However, it was composed of a pair of easy rotatable atropisomers. In the effort to fix the isomerization, a highly potent alkoxy-aminobenzhydrol scaffold was developed. Some of these acquired compounds demonstrating strong cholesterol synthesis inhibitory activities in a rat hepatic cell. Moreover, two of the series compounds exhibited specific plasma lipid-lowering effects in in vivo animal models.
authors.affiliation: Lead Discovery and Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan. ichikawa.masanori.uf@daiichisankyo.co.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Aki
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Masao
authors.initials: M
authors.lastname: Itoh
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Usui
authors.forename: Koji
authors.initials: K
authors.lastname: Terayama
authors.forename: Akira
authors.initials: A
authors.lastname: Kanda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D002144:Callithrix; D003198:Computer Simulation; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D007536:Isomerism; D008297:Male; D023421:Models, Animal; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D001559:Benzhydryl Compounds; D004791:Enzyme Inhibitors; D013186:Farnesyl-Diphosphate Farnesyltransferase; C020225:benzohydrol