Challenges in the development of mGluR5 positive allosteric modulators: The discovery of CPPHA Zhijian Zhao, a, * David D. Wisnoski, a Julie A. O’Brien, b Wei Lemaire, b David L. Williams, Jr., b Marlene A. Jacobson, b Marion Wittman, b Sookhee N. Ha, b Herve Schaffhauser, b Cyrille Sur, b Doug J. Pettibone, b Mark E. Duggan, a P. Jeffrey Conn, b,c George D. Hartman a and Craig W. Lindsley a,c a Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA b Department of Neuroscience, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA c VICB Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA Received 4 October 2006; revised 21 November 2006; accepted 30 November 2006 Available online 3 December 2006 Abstract—This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Bind- ing to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories. Ó 2006 Elsevier Ltd. All rights reserved. Our laboratory recently disclosed the structures and pharmacology of two series of mGluR5 positive alloste- ric modulators (PAMs), represented by DFB (1) and CPPHA (2), and one account of the synthesis, SAR, and in vivo efficacy of the first centrally active mGluR5 PAM, CDPPB (3)(Fig. 1). 1–4 Data acquired with all three series of mGluR5 PAMs, by indirect activation of NMDA receptors, strongly support the NMDA hypofunction hypothesis of schizophrenia. 5 Since these initial reports, CPPHA has proven to be an important pharmacological tool for both our laboratory and a number of other pharmaceutical and academic laborato- ries. 2,6,7 Of particular note is the fact that DFB and CDPPB bind at the same allosteric binding site as the mGluR5 negative allosteric modulator, MPEP; in con- trast, CPPHA does not bind at the MPEP site and therefore interacts with an as yet unknown and distinct allosteric binding site. 1–4 The novel allosteric binding site of CPPHA has engendered unique pharmacology to CPPHA (vide infra) as well as significant challenges in the lead optimization program that led to the discov- ery of CPPHA. This Letter will detail the screening leads and subsequent synthesis and SAR that ultimately led to the discovery of CPPHA, as well as an overview of the pharmacological profile of CPPHA. We screened a portion of our sample collection searching for compounds that selectively potentiated the mGluR5 response to 300 nM glutamate (an EC 20 concentration 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.11.081 Keywords: MGluR5; Allosteric modulator; Potentiation. * Corresponding author. E-mail: zhijian_zhao@merck.com N N F F 1, DFB HN N O O O OH 2, CPPHA N N Cl H N O CN 3, CDPPB Figure 1. mGluR5 positive allosteric modulators (PAMS). Bioorganic & Medicinal Chemistry Letters 17 (2007) 1386–1391