title: Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors.
abstract: To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.
authors.affiliation: Lead Discovery and Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, 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: Hiroyuki
authors.initials: H
authors.lastname: Usui
authors.forename: Hironari
authors.initials: H
authors.lastname: Shimizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Terayama
authors.forename: Akira
authors.initials: A
authors.lastname: Kanda
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
mesh_terms: D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C559078:1-(4-((4-chloro-2-((2-chlorophenyl)(hydroxy)methyl)phenyl)(2,2-dimethylpropyl)amino)-4-oxobutanoyl)piperidine-3-carboxylic acid; D001559:Benzhydryl Compounds; D004791:Enzyme Inhibitors; D010880:Piperidines; D013186:Farnesyl-Diphosphate Farnesyltransferase; C020225:benzohydrol