title: Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor β-selective agonists.
abstract: A novel series of 1,3-bistrifluoromethylcarbinol derivatives that act as liver X receptor (LXR) β-selective agonists was discovered. Structure-activity relationship studies led to the identification of molecule 62, which was more effective (Emax) and selective toward LXRβ than T0901317 and GW3965. Furthermore, 62 decreased LDL-C without elevating the plasma TG level and significantly suppressed the lipid-accumulation area in the aortic arch in a Bio F1B hamster fed a diet high in fat and cholesterol. We demonstrated that our LXRβ agonist would be potentially useful as a hypolipidemic and anti-atherosclerotic agent. In this manuscript, we report the design, synthesis and pharmacology of 1,3-bistrifluoromethylcarbinol derivatives.
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Koura
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Okuda
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kurobuchi
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan. Electronic address: k-sibuya@kowa.co.jp.
authors.forename: Kimiyuki
authors.initials: K
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D000432:Methanol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001565:Benzoates; D001596:Benzylamines; D006845:Hydrocarbons, Fluorinated; D000960:Hypolipidemic Agents; D000071518:Liver X Receptors; D000432:Methanol; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: 1,1-Bistrifluoromethylcarbinol; Anti-atherosclerosis; LDL-C; Liver X receptor (LXR) β-selective