Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain Jun Liang, a, * Richard M. Brochu, b Charles J. Cohen, b Ivy E. Dick, b John P. Felix, b Michael H. Fisher, a Maria L. Garcia, b Gregory J. Kaczorowski, b Kathryn A. Lyons, a Peter T. Meinke, a Birgit T. Priest, b William A. Schmalhofer, b McHardy M. Smith, b Jason W. Tarpley, c Brande S. Williams, b William J. Martin c and William H. Parsons a a Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA b Department of Ion Channels, Merck Research Laboratories, Rahway, NJ 07065, USA c Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA Received 20 December 2004; revised 18 February 2005; accepted 22 February 2005 Available online 4 May 2005 Abstract—A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. System- atic structure–activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use- dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG. Ó 2005 Published by Elsevier Ltd. 1. Introduction It is widely recognized that chronic pain encompasses a number of heterogeneous symptoms, which can gener- ally be characterized as inflammatory or neuropathic, the latter representing a category for which few thera- pies currently exist. Injuries or diseases of the peripheral nervous system can lead to neuropathic pain. 1 Experi- mentally and clinically, such pain states are associated with hyper-excitability and spontaneous action potential firing in peripheral sensory neurons. Voltage-gated sodium channels (Na v 1) underlie the initi- ation and propagation of action potentials in peripheral neurons, and are therefore appealing molecular targets for treating chronic pain. 2 Proof of concept for Na v 1 channels in the clinic has been suggested from the use of blockers such as carbamazepine, lamotrigine, and lidocaine. 3 A shared feature among these treatments for chronic pain is the ability to block sodium channels, and, at therapeutic concentrations, sodium channel block is the only known effect of lidocaine. Several sub- types of sodium channels have been identified, including Na v 1.7 (PN1) 4 and Na v 1.8 (PN3), 5 which are predomi- nantly expressed in the peripheral nervous system and dorsal root ganglion (DRG), 6 and have been implicated in pain transmission pathways. 7 Sodium channel block- ers used to treat chronic pain do not discriminate be- tween Na v 1 subtypes and derive their therapeutic index from their use-dependent properties. The objective of this study was to identify potent, use-dependent, and orally bioavailable sodium channel blockers with good therapeutic windows, that could be developed for treat- ment of chronic pain in patients. 2. Results and discussion Compound 1 (Fig. 1) was first disclosed by scientists at Ciba-Geigy as a highly potent blocker of cardiac sodium channels. 8 This compound was prepared and found to be active against Na v 1.7 in a functional, Volt- age/Ion Probe Reader (VIPR) assay that measures veratridine-induced depolarization in HEK-293 cells stably transfected with Na v 1.7 channels 9 (IC 50 4.0 lM). Compound 1 was also tested in a rat formalin paw model 10 as previously described. 9b In this model, injection of formalin into the hind paw induces two phases of spontaneous pain behavior. Compound 1 re- duced phase II (10–60 min) formalin-induced flinching in a dose-dependent manner when injected locally into 0960-894X/$ - see front matter Ó 2005 Published by Elsevier Ltd. doi:10.1016/j.bmcl.2005.02.093 * Corresponding author. E-mail: jun_liang@merck.com Bioorganic & Medicinal Chemistry Letters 15 (2005) 2943–2947