Synthesis and Evaluation of Diarylthiazole Derivatives That Inhibit Activation of Sterol Regulatory Element-Binding Proteins

Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure–activity relationships led to the...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2011-07, Vol.54 (13), p.4923-4927
Main Authors: Kamisuki, Shinji, Shirakawa, Takashi, Kugimiya, Akira, Abu-Elheiga, Lutfi, Park Choo, Hea-Young, Yamada, Kohei, Shimogawa, Hiroki, Wakil, Salih J, Uesugi, Motonari
Format: Article
Language:English
Subjects:
Animals
Blood Glucose - analysis
CHO Cells
Cricetinae
Cricetulus
Eating - drug effects
Hepatocytes - metabolism
Male
Membranes, Artificial
Mice
Mice, Obese
Permeability
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Solubility
Sterol Regulatory Element Binding Proteins - antagonists & inhibitors
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure–activity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm200304y