Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: Kinetic analysis was initially used to determine the potency of PF-04886847. Biochemical ligand binding assays, immunological methods and calcium flux studies were used to determine the selectivity of the kallikrein inhibitor. In addition, the effect of PF-04886847 on BK-induced relaxation of the rat aortic ring was determined in a model of lipopolysaccharide-induced tissue inflammation. KEY RESULTS: Evidence was obtained in vitro and in situ, indicating that PF-04886847 is a potent and specific inhibitor of plasma kallikrein. PF-04886847 efficiently blocked calcium influx as well as NO and PGI(2) formation mediated through the BK-stimulated B(2) receptor signalling pathway. PF-04886847 blocked kallikrein-induced endothelial-dependent relaxation of isolated rat aortic rings pre-contracted with phenylephrine. CONCLUSIONS AND IMPLICATIONS:
PF-04886847 was shown to be the most potent small molecule inhibitor of plasma kallikrein yet described; it inhibited kallikrein in isolated aortic rings and cultured endothelial cells. Overall, our results indicate that PF-04886847 would be useful for the treatment of kallikrein-mediated inflammatory disorders.
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Authors | D Kolte, Jw Bryant, D Holsworth, J Wang, P Akbari, Gw Gibson, Z Shariat-Madar |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 162
Issue 7
Pg. 1639-49
(Apr 2011)
ISSN: 1476-5381 [Electronic] England |
PMID | 21175583
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Chemical References |
- Aminobenzoates
- Aminopyridines
- Enzyme Inhibitors
- Kininogen, High-Molecular-Weight
- Lipopolysaccharides
- PF 04886847
- Phenylephrine
- Nitric Oxide
- Epoprostenol
- Plasma Kallikrein
- Bradykinin
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Topics |
- Aminobenzoates
(pharmacology)
- Aminopyridines
(pharmacology)
- Animals
- Bradykinin
(metabolism)
- Cells, Cultured
- Endothelial Cells
(drug effects, enzymology, metabolism)
- Enzyme Inhibitors
(pharmacology)
- Epoprostenol
(metabolism)
- Humans
- Inflammation
(drug therapy, enzymology)
- Kinetics
- Kininogen, High-Molecular-Weight
(antagonists & inhibitors, metabolism)
- Lipopolysaccharides
(pharmacology)
- Muscle Contraction
(drug effects)
- Nitric Oxide
(metabolism)
- Phenylephrine
(metabolism, pharmacology)
- Plasma Kallikrein
(antagonists & inhibitors, chemistry, metabolism)
- Rats
- Signal Transduction
(drug effects)
- Substrate Specificity
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