REVIEW PF 8380 is a potent inhibitor of autotaxin, the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), which is up-regulated in many inflammatory conditions, including 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. PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] has an IC(50) of 2.8 nM in an 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.
REFERENCES
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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. A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation, Journal of Pharmacology and Experimental Therapeutics (2010), 334(1), 310-317.
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Mize, Catrina D.; Abbott, Ashley M.; Gacasan, Samantha B.; Parrill, Abby L.; Baker, Daniel L. Ligand-based autotaxin pharmacophore models reflect structure-based docking results, Journal of Molecular Graphics & Modelling (2011), 31, 76-86.
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St-Coeur PD, Ferguson D, Morin P Jr, Touaibia M. PF-8380 and closely related analogs: synthesis and structure-activity relationship towards autotaxin inhibition and glioma cell viability. Arch Pharm (Weinheim). 2013 Feb;346(2):91-7.
[4]
St-Coeur, Patrick-Denis; Ferguson, Dean; Morin, Pier, Jr.; Touaibia, Mohamed; PF-8380 and Closely Related Analogs: Synthesis and Structure-Activity Relationship towards Autotaxin Inhibition and Glioma Cell Viability, Archiv der Pharmazie (Weinheim, Germany) (2013), 346(2), 91-97.
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