1. Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists.
- Author
-
Matsui Y, Yamaguchi T, Yamazaki T, Yoshida M, Arai M, Terasaka N, Honzumi S, Wakabayashi K, Hayashi S, Nakai D, Hanzawa H, and Tamaki K
- Subjects
- Animals, Benzoates administration & dosage, Benzoates chemistry, Dose-Response Relationship, Drug, Humans, Hydrocarbons, Fluorinated administration & dosage, Hydrocarbons, Fluorinated chemistry, Liver X Receptors, Mice, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Benzoates pharmacology, Drug Discovery, Hydrocarbons, Fluorinated pharmacology, Orphan Nuclear Receptors 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF