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Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Jan; Vol. 360 (1), pp. 1-13. Date of Electronic Publication: 2016 Oct 17. - Publication Year :
- 2017
-
Abstract
- Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.<br /> (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Animals
Disease Models, Animal
Enzyme Inhibitors pharmacokinetics
Enzyme Inhibitors therapeutic use
Female
Humans
Male
Mice
Piperazines pharmacokinetics
Piperazines therapeutic use
Enzyme Inhibitors pharmacology
Liver Cirrhosis drug therapy
Liver Cirrhosis enzymology
Phosphoric Diester Hydrolases metabolism
Piperazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 360
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 27754931
- Full Text :
- https://doi.org/10.1124/jpet.116.237156