3-Amino-1,5-benzodiazepinones: Potent, state-dependent sodium channel blockers with anti-epileptic activity Scott B. Hoyt, a, * Clare London, a Matthew J. Wyvratt, a Michael H. Fisher, a Doreen E. Cashen, b John P. Felix, c Maria L. Garcia, c Xiaohua Li, a Kathryn A. Lyons, a D. Euan MacIntyre, b William J. Martin, b Birgit T. Priest, c McHardy M. Smith, c Vivien A. Warren, c Brande S. Williams, c Gregory J. Kaczorowski c and William H. Parsons a a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, RY 123-236, Rahway, NJ 07065-0900, USA b Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA c Department of Ion Channels, Merck Research Laboratories, Rahway, NJ 07065, USA Received 20 December 2007; revised 29 January 2008; accepted 30 January 2008 Available online 7 February 2008 Abstract—A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy. Ó 2008 Elsevier Ltd. All rights reserved. Approximately two dozen drugs are currently marketed for the treatment of epilepsy, a common CNS disorder that afflicts nearly 2% of the world’s population. 1 Some act by sodium or calcium channel blockade, while others function at the GABA A receptor, or by mixed or un- known mechanisms of action. Though a broad range of treatment options is available, an estimated 30% of patients do not respond to any current therapy. 2 Addi- tionally, in patients who do respond, existing drugs of- ten elicit adverse effects such as sedation and neuronal impairment. Epileptic seizures begin with the aberrant firing of action potential bursts in the brain. The initiation and propa- gation of these action potentials typically require the opening of voltage-gated sodium channels (Na v 1.x). Be- cause they can inhibit action potential firing, sodium channel blockers have been investigated as anti-epileptic treatments. Weak blockers such as carbamazepine and lamotrigine have demonstrated clinical anticonvulsant activity, thereby providing validation for this approach (Fig. 1). 3,4 Sodium channel blockers destined for the clinic must in- hibit aberrant neuronal signaling while leaving normal nerve functions intact. We believe that this can be achieved, in large part, via state-dependent channel block. Sodium channels are thought to exist in three main conformational states: resting, open, and inacti- vated. In healthy nerve and cardiac tissue, these chan- nels exist predominantly in the resting state. During seizure, on the other hand, the aberrant firing of high- frequency action potential bursts causes sodium chan- nels to accumulate in the inactivated state. Compounds that selectively bind and stabilize that inactivated state should inhibit aberrant signaling preferentially, thus minimizing the potential for mechanism-based adverse effects. We recently reported the discovery of a structurally novel series of benzazepinone sodium channel blockers. 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.01.123 Keywords: Sodium channel blocker; Na v 1; Epilepsy. * Corresponding author. Tel.: +1 732 594 3753; fax: +1 732 594 5350; e-mail: scott_hoyt@merck.com N N N NH 2 Lamotrigine N H 2 N O Carbamazepine N N H O O NH Boc 1 OCF 3 Cl Cl H 2 N Figure 1. Sodium channel blockers. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 1963–1966