Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor

Joe A. Tran, Wanlong Jiang, Fabio C. Tucci, Beth A. Fleck, Jenny Wen, Yang Sai, Ajay Madan, Kung Chen Ta, Stacy Markison, Alan C. Foster, Sam R. Hoare, Daniel Marks, John Harman, Caroline W. Chen, Melissa Arellano, Dragan Marinkovic, Haig Bozigian, John Saunders, Chen Chen

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Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a Ki value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.

Original languageEnglish (US)
Pages (from-to)6356-6366
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number25
Publication statusPublished - Dec 15 2007


ASJC Scopus subject areas

  • Organic Chemistry

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