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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 25, 2006; DOI: 10.1124/jpet.106.104737

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Received for publication March 16, 2006.
Revised May 23, 2006.
Accepted for publication May 23, 2006.

Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA): a potent, broad-spectrum state-dependent sodium channel blocker for treating pain states

Victor I. Ilyin 1*, James D. Pomonis 2, Garth T. Whiteside 3, James E. Harrison 3, Michelle S. Pearson 4, Lilly Mark 5, Paul I. Turchin 6, Susan Gottshall 2, Richard B. Carter 7, Phong Nguyen 8, Derk J. Hogenkamp 9, Shakira Olanrewaju 1, Elfrida Benjamin 10, Richard M. Woodward 11

1 Purdue Pharma, L.P. 2 Algos Therapeutics, 1246 University Ave W, Suite 205, St. Paul, MN 55104 3 Wyeth Research, CN 8000, Princeton, NJ 08543 4 Merck and Company, Sumneytown Pike, West Point, PA 19486 5 Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033 6 37 York Dr, Apt 3B, Edison, NJ 08817 7 Novartis Pharmaceutical Corporation, One Health Plaza, East Hanover, NJ 07936 8 Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612 9 Department of Pharmacology, University of California, Irvine, CA 92697 10 Amicus Therapeutics, 6 Cedar Brook Drive, Cranbury, NJ 08512 11 Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341

* Address correspondence to: E-mail: victor.ilyin{at}pharma.com

Abstract

Voltage-gated Na+ channels play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na+ channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain, however their therapeutic utility is compromised by CNS side effects. We reasoned that it may be possible to gain superior control over pain states, and in particular a better therapeutic index, by designing broad-spectrum Na+ channel blockers with higher potency, faster onset kinetics and greater levels of state-dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analogue of the state-dependent Na+ channel blocker V102862 (4-(4-fluorophenoxy)benzaldehyde semicarbazone). Tested on recombinant rat Nav1.2 channels and native Na+ currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000-times more potent, had 2000-fold faster binding kinetics and ≥10-fold higher levels of state-dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1-3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and post-incisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high potency, broad-spectrum state-dependent Na+ channel blockers will have clinical utility for treating neuropathic, inflammatory and post-surgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na+ channel blockers may lead to improved pain therapeutics.


Key words: FCA pain model, clinical comparators, partial sciatic nerve ligation model, post-incisional pain model, recombinant and native Na channels, state-dependent inhibition




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