Melanocortin subtype-4 receptor agonists containing a piperazine core with substituted aryl sulfonamides Christopher Fotsch, * Nianhe Han, Premilla Arasasingham, Yunxin Bo, Michelle Carmouche, Ning Chen, James Davis, Martin H. Goldberg, Clarence Hale, Feng-Yin Hsieh, Michael G. Kelly, Qingyian Liu, Mark H. Norman, Duncan M. Smith, Markian Stec, Nuria Tamayo, Ning Xi, Shimin Xu, Anthony W. Bannon and James W. Baumgartner Departments of Chemistry Research and Discovery and Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mailstop 29-1-B, Thousand Oaks, CA 91320, USA Received 13 December 2004; revised 24 January 2005; accepted 25 January 2005 Abstract—The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho- substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg 1 in fasted mice. Ó 2005 Elsevier Ltd. All rights reserved. The melanocortin-4 receptor (MC4R) is a G-protein coupled receptor expressed in the hypothalamus, which has been shown to regulate feeding behavior. 1,2 Agonists to the receptor have been shown to decrease feeding in rodents. 3 Conversely, feeding increased when rodents were treated with MC4R antagonists. 4,5 In addition, mice lacking the gene encoding MC4R are obese and hyperphagic. 2 In humans, MC4R polymorphisms that impair receptor function have been linked to obesity. 6 More recently, experiments have been conducted that link MC4R to sexual arousal. 7,8 Agonists to MC4R cause an increase in the number of penile erection in rats. 7 In addition, administration of a potent melanocor- tin receptor peptide agonist increases the number of erections in men with erectile dysfunction (ED). 8 Be- cause of the evidence supporting MC4R as a key medi- ator in two physiological functions, we set out to identify small molecule agonists for MC4R that might be used as therapies for either obesity or ED. In the past few years, several patent applications 9 and articles in the literature 10 have appeared that contain MC4R agonists with either the piperidine or piperazine core (see Fig. 1). In many of the published structures, the piperidine or piperazine is appended with two amino acids: para-chloro-D-phenylalanine (pCl-D- D- Phe) and D-1,2,3,4-tetrahydro-3-isoquinoline (D-Tic). In 2002, a research group at Merck published agonists that contained this dipeptide appended onto a piperidine core. 10a Compound 1 from this report was a low-nano- molar functional agonist and was several fold more selective for MC4R over two other receptor subtypes, MC3R and MC5R. In addition, compound 1 showed both anti-feeding effects and increased the number of erections in rats. Scientists at Lilly 10b and Neurocrine Biosciences 10c–e also independently identified potent and selective MC4R agonists that contained a piper- azine appended to the pCl-D- D- Phe, D-Tic dipeptide. In our own studies, we identified MC4R agonists that con- tained the piperazine core with the pCl-D-Phe, and L-Tic dipeptide (compound 2). The piperazine on 2 is ap- pended with a ortho-substituted aryl sulfonamide group. Compound 2 was potent at MC4R and selective over MC3R, but 2 was only 21-fold selectivity for MC4R over MC5R. We wanted to further explore the 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.01.060 Keywords: Melanocortin subtype 4 receptor; Piperazine; Feeding. * Corresponding author. Tel.: +1 805 447 7746; fax: +1 805 480 1337; e-mail: cfotsch@amgen.com Bioorganic & Medicinal Chemistry Letters 15 (2005) 1623–1627