title: Discovery of DF-461, a Potent Squalene Synthase Inhibitor.
abstract: We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ohtsuka
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohki
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ota
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Itoh
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ishigai
authors.forename: Koji
authors.initials: K
authors.lastname: Terayama
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kanda
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Usui
keywords: Squalene synthase; dyslipidemia; inhibitor; triazolobenzoxazepine