Discovery of (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione, a readily available and orally active glitazone for the treatment of concanavalin A-induced acute liver injury of BALB/c mice.
A large amount of evidence suggests that monocytes/macrophages infiltration is implicated in a variety of inflammatory diseases including acute liver injury. Monocyte chemoattractant protein 1 (MCP-1) plays a crucial role in the process of macrophages recruitment. We herein presented a small-molecule library and a feasible quick screening method of evaluating potency of inhibition of chemotaxis of RAW264.7 cells stimulated by MCP-1. Fifty-three small molecules were synthesized and screened, and four compounds (2g, 2h, 4f, and 6h) showed inhibitory effects with IC(50) values range from 0.72 to 20.47 microM, with compound 4f being the most efficient. Further in vivo studies demonstrated that oral administration of 2g, 2h, 4f, or 6h decreases, most significantly for 4f, the serum levels of alanine aminotransaminase (ALT) and asparate aminotransaminase (AST) in ConA-induced acute livery injury BALB/c mice. Histopathological evaluation liver sections confirmed 4f as a potent, orally active compound for hepatoprotective effects against ConA-induced acute liver injury in BALB/c mice.
Luo
Youfu
Y
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China.
Ma
Liang
L
Zheng
Hao
H
Chen
Lijuan
L
Li
Rui
R
He
Chunmei
C
Yang
Shengyong
S
Ye
Xia
X
Chen
Zhizhi
Z
Li
Zicheng
Z
Gao
Yan
Y
Han
Jing
J
He
Gu
G
Yang
Li
L
Wei
Yuquan
Y
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005260:Female; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D051379:Mice; D008807:Mice, Inbred BALB C; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C546799:5-(4-methoxybenzylidene)thiazolidine-2,4-dione; D054852:Small Molecule Libraries; D045162:Thiazolidinediones; D003208:Concanavalin A