Structure–Activity Relationship Studies on 2-Heteroaryl-4- arylimidazoles NPY5 Receptor Antagonists Richard L. Elliott, a, * Robert M. Oliver, a Janet A. LaFlamme, a Melissa L. Gillaspy, a Marlys Hammond, a Richard F. Hank, a Tristan S. Maurer, a Demetria L. Baker, a Paul A. DaSilva-Jardine, a Ralph W. Stevenson, a Christine M. Mack b and James V. Cassella b a Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA b Neurogen Corporation, Branford, CT 06405, USA Received 18 December 2002; accepted 4 June 2003 Abstract—A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity. # 2003 Elsevier Ltd. All rights reserved. Neuropeptide Y (NPY) is a 36 amino acid peptide that has been implicated in modulating food intake in ani- mals, including humans. NPY, which is found in both the periphery and CNS, mediates its biological effects via six receptor subtypes (NPY1-NPY6). It is currently believed that NPY’s orexigenic effects are mediated by either the NPY1 or NPY5 receptor subtype, or possibly a combination of both receptor subtypes. Evidence supporting the role of the NPY5 receptor subtype in regulating food intake and body weight includes the finding that the orexigenic effect of peptide analogues of NPY correlate with affinity for the NPY5 receptor, 1 the anatomical location and physiological regulation of NPY5 receptors in areas of the CNS relevant to feed- ing, 2 and the determination that NPY5 antisense oligo- deoxynulceotides have anorectic effects in rodents. 3 The robust orexigenic responses seen in animals when dosed with NPY and NPY agonists has led to great interest in identifying and developing NPY1 and/or NPY5 antagonists for the treatment of obesity. Compound 1, 2,5-diphenyl-1H-imidazole, was identified from a high-throughput screen for NPY5 antagonists. Although this compound had fairly good potency for the NPY5 receptor (34 nM, see Table 1)itwasfoundto have poor metabolic stability and low water solubility. Herein, we report our SAR studies that were under- taken in an effort to improve the in vitro potency, phy- siochemical properties, and pharmacokinetic properties of this series. The synthesis of the 2-heteroaryl-4-arylimidazoles uti- lized the condensation of a heteroaryl amidine II with an a-bromo arylketone III (Scheme 1). The requisite amidines II, when not commercially available, were generated by treatment of the corresponding heteroaryl nitrile I with lithium bis(trimethylsilyl)amide at room temperature, and subsequently used in situ in the con- densation with the bromoketone III to afford the desired imidazole. The bromoketones III were either commercially available or synthesized via bromination of the corresponding aryl ketone. The NPY-5 receptor binding and functional antagonism activities for these compounds are shown in Table 1. Initial efforts to improve the potency and water solubi- lity of these compounds led to the synthesis of 2, 3, and 4, where the 2-phenyl moiety has been replaced by a 2-, 3-, and 4-pyridyl ring, respectively. Although com- pounds 2–4 had significantly lower binding potency 0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00747-9 Bioorganic & Medicinal Chemistry Letters 13 (2003) 3593–3596 *Corresponding author. Fax: +1-860-715-8069; e-mail: richard_l_ elliott@groton.pfizer.com