Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists Kevin T. Nguyen, a, * Christopher F. Claiborne, a John A. McCauley, a Brian E. Libby, a David A. Claremon, a Rodney A. Bednar, b Scott D. Mosser, b Stanley L. Gaul, b Thomas M. Connolly, b Cindra L. Condra, b Bohumil Bednar, b Gary L. Stump, c Joseph J. Lynch, c Kenneth S. Koblan b and Nigel J. Liverton a a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA b Department of Pain Research, Merck Research Laboratories, West Point, PA 19486, USA c Department of Stroke and Neurodegeneration, Merck Research Laboratories, West Point, PA 19486, USA Received 20 March 2007; revised 24 April 2007; accepted 25 April 2007 Available online 29 April 2007 Abstract—A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain. Ó 2007 Elsevier Ltd. All rights reserved. The N-methyl-D-aspartate (NMDA) receptor is cur- rently the subject of extensive investigation because of its high therapeutic potential for the treatment of a large number of disease states including stroke, epilepsy, neu- ropathic pain, Alzheimer’s disease and Parkinson’s dis- ease. 1 The NMDA channel is a heterooligomeric complex composed of up to three different subunits NR1, NR2 and NR3. NR1 has at least eight isoforms (NR1a-h), NR2 has four distinct subtypes (NR2A-D) and NR3 has 2 subtypes (NR3A and B). Ifenprodil (1, Fig. 1), an antagonist that binds selectively to the NR2B subunit, can effectively modulate ion flux and shows efficacy in animal models of pain. 2,3 In addi- tion, ifenprodil exhibits diminished CNS and locomotor side effects in animal models when compared with non- selective NMDA antagonists. 4 Due to this intriguing biological profile, the ifenprodil binding site on the NR2B subunit has become a highly studied target. 5,6 To date, a number of compounds have been shown to have NR2B subtype selectivity, including CP-101,606 (2) 7 and Ro25-6981 (3). 8 In a previous communication, 9 we reported phenyl ami- dine (4, Fig. 2) as an orally efficacious NR2B-selective NMDA receptor antagonist. Indole amidine 5 has re- cently also been reported to be a potent NR2B/NMDA antagonist. 10 In this communication, we report a novel series of cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists. Four different classes of cyclic amidines were synthe- sized. The results of the NR2B binding and functional assays (calcium ion-flux) 11 and calculated pK a for se- lected cyclic amidines are summarized in Table 1. 12,13 6-Phenyl-2-[4-(trifluoromethoxy)phenyl]-1,4,5,6-tetrahy- dropyrimidin-5-ol (6, Scheme 1) was synthesized from 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.04.084 Keywords: Cyclic benzamidines; NR2B-selective NMDA. * Corresponding author. Tel.: +1 215 652 9357; fax: +1 215 652 3971; e-mail: kevin_nguyen@merck.com N OH Ifenprodil (1) CP-101,606 (2) N Ro 25-6981(3) OH OH OH OH OH OH N Figure 1. Structures of NR2B-selective NMDA receptor antagonists. Bioorganic & Medicinal Chemistry Letters 17 (2007) 3997–4000