3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: A novel series of mGluR2 positive allosteric modulators Lei Zhang * , Bruce N. Rogers, Allen J. Duplantier, Stanley F. McHardy, Ivan Efremov, Helen Berke, Weimin Qian, Andy Q. Zhang, Noha Maklad, John Candler, Angela C. Doran, John T. Lazzaro Jr., Alan H. Ganong Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA article info Article history: Received 17 July 2008 Revised 3 September 2008 Accepted 5 September 2008 Available online 10 September 2008 Keywords: mGluR2 Positive allosteric modulators Potentiators Anxiety Schizophrenia abstract The synthesis and structure–activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza- bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs). Ó 2008 Elsevier Ltd. All rights reserved. The metabotropic glutamate receptors (mGluRs) belong to fam- ily C of GPCRs characterized by a large extracellular bi-lobed ago- nist binding site connected to a heptahelical transmembrane (7TM) domain through a cysteine-rich linker. 1 These receptors are typically subdivided into three groups based on structural homology and signal transduction pathways. 2 Group II are com- prised of mGluR2 and mGluR3 which are both negatively coupled to adenylate cyclase. Efficacy observed in preclinical animal mod- els and human clinical trials with known dual mGluR2/3 agonists (e.g., LY-354740) provides solid support of group II mGluRs as no- vel targets for the treatment of anxiety, 3 psychosis, 4 convulsive disorders, 5 Parkinson’s disease, 6 neurodegeneration, 7 and pain. 8 Tremendous excitement in this field has been generated since the report that LY 2140023, a pro-drug of mGluR2/3 agonist LY- 404039, demonstrated efficacy against positive and negative symptoms in a 4-week phase IIb schizophrenia trial. 9 Due to the high degree of homology in the orthosteric sites of group II mGlu receptors, selective mGluR2 agonists have yet to be discovered. Moreover, known direct agonists are typically ami- no acid analogs, 10 which can limit their utility in pharmacological studies due to poor physicochemical properties and low CNS expo- sure. Positive allosteric modulators (PAMs), in comparison, bind in the transmembrane domain where there is much less homology among different subtypes, thus providing an opportunity to achieve subtype selectivity. Furthermore, the large number of structural diverse, non-amino acid allosteric modulators of mGluRs found to date 11 hold promise of identifying mGluR2 PAMs with suitable physicochemical properties for CNS exposure. Herein the discovery and structure–activity relationship of a novel series of mGluR2 PAMs, 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan- 6-yl)methyl ethers, are described. An in-house high throughput screening campaign using a func- tional FLIPR assay 12 yielded several leads featuring a [3.1.0] azabi- cyclic core, as represented by compound 1 (Fig. 1). Compound 1 displays potent functional activity (mGluR2 EC 50 = 24 nM) and good brain penetration (brain/plasma = 2). 13 However, further pharmacokinetic (PK) profiling revealed high in vitro clearance in rat and human liver microsomes (r-CLh: >65.7 ml/min/kg; h-CLh: 14.2 ml/min/kg). 14 Moreover, compound 1 has low absorption (5%) and oral bioavailability (<2%), 15 potentially due to poor aque- ous solubility of 1 observed during sample formulation. In light of these results, our chemistry efforts were focused on developing a structure–activity relationship around the 3-aza-bicyclo[3.1.0]hex- 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.09.026 * Corresponding author. Tel.: +1 860 441 4116; fax: +1 860 715 2350. E-mail address: Lei.Zhang3@pfizer.com (L. Zhang). N H H O N N 1 Figure 1. The original HTS lead, compound 1. Bioorganic & Medicinal Chemistry Letters 18 (2008) 5493–5496 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl