A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model.
Abstract | BACKGROUND AND PURPOSE: The aim of this study was to assess the potential of an antagonist selective for the lysophosphatidic acid receptor, LPA(1), in treating lung fibrosis We evaluated the in vitro and in vivo pharmacological properties of the high affinity, selective, oral LPA(1)-antagonist (4'-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl- isoxazol-5-yl}- biphenyl-4-yl)- acetic acid (AM966). EXPERIMENTAL APPROACH: The potency and selectivity of AM966 for LPA(1) receptors was determined in vitro by calcium flux and cell chemotaxis assays using recombinant and native cell cultures. The in vivo efficacy of AM966 to reduce tissue injury, vascular leakage, inflammation and fibrosis was assessed at several time points in the mouse bleomycin model. KEY RESULTS: CONCLUSIONS AND IMPLICATIONS:
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Authors | J S Swaney, C Chapman, L D Correa, K J Stebbins, R A Bundey, P C Prodanovich, P Fagan, C S Baccei, A M Santini, J H Hutchinson, T J Seiders, T A Parr, P Prasit, J F Evans, D S Lorrain |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 160
Issue 7
Pg. 1699-713
(Aug 2010)
ISSN: 1476-5381 [Electronic] England |
PMID | 20649573
(Publication Type: Journal Article)
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Chemical References |
- (4'-(4-(1-(2-chlorophenyl)ethoxycarbonylamino)-3-methylisoxazol-5-yl)biphenyl-4-yl)acetic acid
- Carbamates
- Phenylacetates
- Receptors, Lysophosphatidic Acid
- Bleomycin
- Collagen
- Calcium
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Topics |
- Administration, Oral
- Animals
- Bleomycin
(pharmacology)
- Bronchoalveolar Lavage Fluid
(chemistry)
- CHO Cells
- Calcium
(metabolism)
- Carbamates
(administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
- Cell Line, Tumor
- Chemotaxis
(drug effects)
- Collagen
(metabolism)
- Cricetinae
- Cricetulus
- Disease Models, Animal
- Female
- Fibroblasts
(cytology, drug effects, metabolism)
- Humans
- Lung
(drug effects, metabolism, pathology)
- Mice
- Mice, Inbred C57BL
- Phenylacetates
(administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
- Pulmonary Fibrosis
(drug therapy, metabolism, pathology)
- Rats
- Receptors, Lysophosphatidic Acid
(antagonists & inhibitors, genetics)
- Transfection
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