title: Discovery of novel tricyclic compounds as squalene synthase inhibitors.
abstract: In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.
authors.affiliation: Lead Discovery and Optimization Research Laboratories I, R&D Division, 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: Masami
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohki
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.forename: Masao
authors.initials: M
authors.lastname: Itoh
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Usui
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
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002144:Callithrix; D020134:Catalytic Domain; D002478:Cells, Cultured; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D001559:Benzhydryl Compounds; D004791:Enzyme Inhibitors; D013186:Farnesyl-Diphosphate Farnesyltransferase; C020225:benzohydrol