title: Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists.
abstract: To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.
authors.affiliation: Daiichi Sankyo RD Novare Co., Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: matsui.yumi.gk@rdn.daiichisankyo.co.jp.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
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: Arai
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Terasaka
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Honzumi
authors.affiliation: Daiichi Sankyo RD Novare Co., Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakabayashi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shinko
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.affiliation: Daiichi Sankyo RD Novare Co., Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hanzawa
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: tamaki.kazuhiko.s2@daiichisankyo.co.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001565:Benzoates; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C000607828:tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoate
keywords: Atherosclerosis; LXR agonists; Liver X receptors; Structure-based drug design; tert-Butyl benzoate