Novel non-peptidic neuropeptide Y Y 2 receptor antagonists Jill A. Jablonowski, a, * Wenying Chai, a Xiaobing Li, c Dale A. Rudolph, a William V. Murray, c Mark A. Youngman, b Scott L. Dax, b Diane Nepomuceno, a Pascal Bonaventure, a Timothy W. Lovenberg a and Nicholas I. Carruthers a a Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210Merryfield Row, San Diego, CA 92121, USA b Johnson & Johnson Pharmaceutical Research and Development, L.L.C, Welsh and Mckean Roads, PO Box 776, Spring House, PA 19477, USA c Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA Received 13 November 2003; accepted 10 December 2003 Abstract—Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y 2 (NPY Y 2 ) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed. # 2003 Elsevier Ltd. All rights reserved. Neuropeptide Y (NPY) is a 36 amino acid C-amidated peptide, which is highly expressed in both the central and peripheral systems. 1 The high abundance of NPY in the brain and its localization suggests the involvement of NPY in a variety of physiological processes such as anxiety, food intake, water consumption, circadian rhythms, hormone release, learning and memory. 1 Pharmacological and molecular biological studies on NPY identified five NPY receptors (Y 1 ,Y 2 ,Y 4 ,Y 5 and Y 6 ). 2,3 While most medicinal chemistry efforts have focused on the Y 1 and Y 5 receptors, we chose to develop small molecule modulators of the Y 2 receptor. 4 The Y 2 receptor is found in several areas of the brain including the septum, hypothalamus, hippocampus, substantia nigra and cerebellum. 1 Recently this receptor has gained considerable interest because of its possible role in the regulation of food intake 5 7 and bone formation. 8,9 Previous work in the discovery of NPY Y 2 ligands includes the research of Grouzmann and co-workers. They described a peptide-based ligand, T4-[NPY 33- 36] 4 , which showed considerable affinity (IC 50 =67 nM) for the NPY Y 2 receptor. 10 Also, Doods and co-workers reported on BIIE0246, which also binds to the NPY Y 2 receptor with good affinity (IC 50 =3.3 nM). 11 However, the therapeutic potential of these compounds may be limited due to their peptidic nature and high molecular weight. Following the set-up and validation of a neuropeptide Y Y 2 receptor binding assay, 12 high throughput screening of our corporate compound collection was undertaken. A series of small molecule Y 2 ligands, exemplified by piperidinylindoline cinnamide JNJ-2765074 (1), (IC 50 =4 mM) were identified and a medicinal chemistry program was initiated to evaluate the SAR for these Y 2 ligands. The piperidinylindoline cinnamide can be dissected into three readily prepared fragments and the general syn- thetic method for the preparation of analogues is shown in Scheme 1. 13 We found it necessary to initially couple the indoline portion (3) with the piperidone moiety (2), followed by attachment to the cinnamide residue (5). Attempts to prepare our analogues by combining the indole (3) with the cinnamide portion (5), followed by coupling to the piperidinyl moiety (2) were unsuccessful. The role of the acetyl substituted indoline ring was investigated initially, as shown in Table 1, and it was determined that N-1 substituted analogues such as for- myl analogue 8, 14 acetyl acetate compound 9, glyoxylate 10, and N-methyl substituted indoline 11 retained bind- ing activity that was comparable to the lead. All other analogues including unsubstituted indoline 12, and the methylsulfonyl 13 and the trifluoromethyl acetyl 14 0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2003.12.057 Bioorganic & Medicinal Chemistry Letters 14 (2004) 1239–1242 * Corresponding author. Tel.: +1-858-784-3011; fax: +1-858-450- 2049; e-mail: jjablono@prdus.jnj.com