Optimization of azepanone calcitonin gene-related peptide (CGRP) receptor antagonists: Development of novel spiropiperidines Christopher S. Burgey a, * , Craig M. Potteiger a , James Z. Deng a , Scott D. Mosser b , Christopher A. Salvatore b , Sean Yu c , Shane Roller c , Stefanie A. Kane b , Joseph P. Vacca a , Theresa M. Williams a a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA b Department of Pain and Migraine Research, Merck Research Laboratories, West Point, PA 19486, USA c Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA article info Article history: Received 20 August 2009 Revised 16 September 2009 Accepted 17 September 2009 Available online 22 September 2009 Keywords: CGRP CGRP receptor antagonists Migraine Calcitonin gene-related peptide abstract Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism. Ó 2009 Elsevier Ltd. All rights reserved. Within the field of antimigraine therapy, the development of novel drugs with enhanced safety profiles and/or improved efficacy is a current major focus. The triptan class of 5-HT 1B/1D receptor agonists represents the current standard of treatment for a mi- graine attack; however, these compounds are contraindicated in patients with cardiovascular disease. 1 Calcitonin gene-related pep- tide (CGRP) has been proposed to be a key neuropeptide in the pathogenesis of migraine headache, engendering hope for the development of receptor antagonists as therapeutics devoid of the cardiovascular effects associated with current migraine treatments. 2 We have undertaken a research program aimed at identifying small-molecule CGRP receptor antagonists suitable for oral admin- istration during a migraine attack. 3 A recent report from these lab- oratories detailed the identification of a series of potent, orally bioavailable, small-molecule, azepanone-based CGRP receptor antagonists. 4 A development candidate was selected from this ser- ies (Fig. 1, telcagepant, MK-0974) and this compound has recently demonstrated efficacy similar to a triptan in a phase 3 migraine clinical trial; importantly, overall adverse event rates were compa- rable to placebo and lower than the triptan positive comparator. 5 Research efforts have continued within the azepanone series, focusing on the identification of compounds with improved profiles. One area targeted for optimization was the elimination/ modification of areas of the lead molecule known to be susceptible to oxidative metabolism (i.e., metabolic soft-spots). The primary site of metabolism is the piperidine-based ‘privileged structure’. For example, telcagepant undergoes N-oxidation to afford 1 and N-dealkylation to produce hydroxypiperidine 2. These pathways are manifested in the low oral bioavailability in rhesus, primarily due to intestinal first-pass metabolism (Fig. 1). 6 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.09.066 * Corresponding author. E-mail address: christopher_burgey@merck.com (C.S. Burgey). N H N N O N NH O N N N NH O N O F F F 3 C N OH O K i = 0.8 nM cAMP IC 50 = 2 nM +50% HS IC 50 = 11 nM telcagepant (MK-0974) 1 K i = 66 nM 2 K i = 5000 nM metabolism Figure 1. Bioorganic & Medicinal Chemistry Letters 19 (2009) 6368–6372 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl