Pyrrolidines as potent functional agonists of the human melanocortin-4 receptor Joe A. Tran, a Caroline W. Chen, a Wanlong Jiang, a Fabio C. Tucci, a,  Beth A. Fleck, b Dragan Marinkovic, a Melissa Arellano a and Chen Chen a, * a Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA b Department of Pharmacology, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA Received 4 June 2007; revised 22 June 2007; accepted 28 June 2007 Available online 4 July 2007 Abstract—A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example, 28c had a K i of 13 nM in binding affinity and EC 50 of 6.9 nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand a-MSH. Ó 2007 Elsevier Ltd. All rights reserved. The melanocortin-4 receptor (MC4R) is a member of the G-protein-coupled receptor superfamily, and plays an important role in regulating feeding behavior and other biological functions. 1 Therefore, MC4R agonists have been extensively studied in an effort to discover small molecules for the treatment of obesity. 2 Several MC4R agonists from different chemical classes have been reported. 3 For example, compound 1 (Fig. 1), 4 characterized as a potent and selective MC4R agonist, has demonstrated efficacy in obesity models in rodents. 5 A series of phenylpiperazines 2–5 have been reported by several research groups. Richardson and coworkers have reported that compound 2 (EC 50 = 71 nM) is mod- erately active, while its imidazole derivative 4 (EC 50 = 14 nM) possesses potent agonist activity at hMC4R. 6 The methanesulfonamide 3 as an MC4R ago- nist has been reported by Dyck, 7 Richardson, 6 and Fotsch and coworkers. 8 In addition, a N,N-dimethylam- inomethyl analog 5 (K i = 60 nM, EC 50 = 7 nM) exhibits good binding affinity and agonist potency. 6 We have also found that an additional amino group at this site improves the interaction of this series of compounds with the receptor. 9 For example, compound 6 (K i = 6.4 nM, EC 50 = 3.8 nM) is a 100-fold more potent agonist than the sulfonamide 3 (EC 50 = 380 nM) in our assay. 7 Recently, we have discovered that benzylamine with a small alkyl group at the benzylic position in- creases the binding affinity of a series of antagonists such as 8. 10 Ujjainwalla has recently reported that a series of pyrroli- dines are potent and selective MC4R agonists. 11 For example, compound 9 has an EC 50 of 2 nM in a MC4R functional assay and an IC 50 of 14 nM in a binding assay. One advantage of this compound is that it is less peptide- like than 1. Here we report our exploratory work on the combination of the pyrrolidine moiety in 9 with the piperazinbenzylamine functionality in our MC4R antag- onist template 8 to synthesize potent MC4R agonists. The trans-N-isopropylpyrrolidine carboxylic amides 14–19 were synthesized by the reaction of trans-1-tert- butoxycarbonyl-4-(4-chlorophenyl)pyrrolidine-3-car- boxylic acid 11 with a variety of phenylpiperazines 12a– f under coupling conditions, followed by deprotec- tion of the Boc-group of 13 and reductive alkylation with acetone as shown in Scheme 1. For compounds 17–19, 12 an HCl/MeOH treatment was required to remove the tert-butylsulfinyl group before purification (Scheme 1). Reduction of benzonitrile 15 with sodium borohydride catalyzed with nickel chloride afforded the benzylamine 20a, which was converted to the corresponding methanesulfonamide 20b. Reductive alkylation of 20a with isobutyraldehyde provided the secondary amine 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.06.088 Keywords: Pyrrolidine; Melanocortin-4 receptor; Agonist; Synthesis. * Corresponding author. Tel.: +1 858 617 7600; fax: +1 858 617 7967; e-mail: cchen@neurocrine.com   Present address: Department of Medicinal Chemistry, Tanabe Research Laboratories, USA, Inc., 4540 Towne Centre Ct., San Diego, CA 92121, USA. Bioorganic & Medicinal Chemistry Letters 17 (2007) 5165–5170