Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor β-selective agonists

Minoru Koura; Takayuki Matsuda; Ayumu Okuda; Yuichiro Watanabe; Yuki Yamaguchi; Sayaka Kurobuchi; Yuuki Matsumoto; Kimiyuki Shibuya

doi:10.1016/j.bmcl.2015.04.080

Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor β-selective agonists

Bioorg Med Chem Lett. 2015 Jul 1;25(13):2668-74. doi: 10.1016/j.bmcl.2015.04.080. Epub 2015 May 5.

Authors

Minoru Koura¹, Takayuki Matsuda¹, Ayumu Okuda¹, Yuichiro Watanabe¹, Yuki Yamaguchi¹, Sayaka Kurobuchi¹, Yuuki Matsumoto¹, Kimiyuki Shibuya²

Affiliations

¹ Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
² 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.

PMID: 25998501
DOI: 10.1016/j.bmcl.2015.04.080

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.

Keywords: 1,1-Bistrifluoromethylcarbinol; Anti-atherosclerosis; LDL-C; Liver X receptor (LXR) β-selective.

MeSH terms

Animals
Atherosclerosis / drug therapy
Benzoates / chemistry
Benzoates / pharmacology
Benzylamines / chemistry
Benzylamines / pharmacology
Cricetinae
Drug Design
Humans
Hydrocarbons, Fluorinated / chemical synthesis
Hydrocarbons, Fluorinated / chemistry
Hydrocarbons, Fluorinated / pharmacology
Hypolipidemic Agents / chemical synthesis
Hypolipidemic Agents / chemistry
Hypolipidemic Agents / pharmacology
In Vitro Techniques
Lipid Metabolism / drug effects
Liver / drug effects
Liver / metabolism
Liver X Receptors
Male
Methanol / analogs & derivatives*
Methanol / chemical synthesis
Methanol / pharmacology
Mice
Orphan Nuclear Receptors / agonists*
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

Benzoates
Benzylamines
GW 3965
Hydrocarbons, Fluorinated
Hypolipidemic Agents
Liver X Receptors
Orphan Nuclear Receptors
Sulfonamides
T0901317
Methanol