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A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation.

Authors: Gierse, J  Thorarensen, A  Beltey, K  Bradshaw-Pierce, E  Cortes-Burgos, L  Hall, T  Johnston, A  Murphy, M  Nemirovskiy, O  Ogawa, S  Pegg, L  Pelc, M  Prinsen, M  Schnute, M  Wendling, J  Wene, S  Weinberg, R  Wittwer, A  Zweifel, B  Masferrer, J 
Citation: Gierse J, etal., J Pharmacol Exp Ther. 2010 Jul;334(1):310-7. doi: 10.1124/jpet.110.165845. Epub 2010 Apr 14.
Pubmed: (View Article at PubMed) PMID:20392816
DOI: Full-text: DOI:10.1124/jpet.110.165845

Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.


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RGD Object Information
RGD ID: 9685429
Created: 2015-01-08
Species: All species
Last Modified: 2015-01-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.