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Serendipitous discovery of a new class of agonists for the melanocortin 1 and 4 receptors and a new class of cyclophanes |
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| Authors: | Conde-Frieboes Kilian Ankersen Michael Breinholt Jens Hansen Birgit Sehested Raun Kirsten Thøgersen Henning Wulff Birgitte S |
| Institution: | a Department of Protein & Peptide Chemistry, Novo Nordisk, Novo Nordisk Park, 2760 Måløv, Denmark b CMR—Clinical Pharmacology Research, Novo Nordisk Inc., 100 College Road West, Princeton, NJ 08540, USA c Protein Structure and Biophysics, Novo Nordisk, Novo Nordisk Park, 2760 Måløv, Denmark d Clinical Pharmacology, Novo Nordisk, 2860 Søborg, Denmark e Department of Pharmacology, Novo Nordisk, Novo Nordisk Park, 2760 Måløv, Denmark f Structure, Novo Nordisk, Novo Nordisk Park, 2760 Måløv, Denmark g Department of GLP-1 & Obesity Biology, Novo Nordisk, Novo Nordisk Park, 2760 Måløv, Denmark |
| Abstract: | A new class of melanocortin 4 receptor (MC4r) agonists was discovered from an unexpected sidereaction in which formaldehyde caused cyclization. These cyclophanes were found to be sub micromolar agonists of the MC1 and MC4 and were less potent on the MC3 and MC5 receptor. They were shown to compete with the peptidic antagonist SHU9119 for binding to the MC4 receptor. In an acute feeding study in Sprague Dawley rats, food intake was reduced more than 50% versus vehicle after 3 h at a dose of 1 mg/kg. |
| Keywords: | Melanocortin receptor 4 Agonist Cyclophane Combinatorial chemistry Obesity |
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