Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists

Chen Chen, Fabio C. Tucci, Wanlong Jiang, Joe A. Tran, Beth A. Fleck, Sam R. Hoare, Jenny Wen, Takung Chen, Michael Johns, Stacy Markison, Alan C. Foster, Dragan Marinkovic, Caroline W. Chen, Melissa Arellano, John Harman, John Saunders, Haig Bozigian, Daniel Marks

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


A series of 2-piperazine-α-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1 mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20 mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.

Original languageEnglish (US)
Pages (from-to)5606-5618
Number of pages13
JournalBioorganic and Medicinal Chemistry
Issue number10
StatePublished - May 15 2008


  • Antagonist
  • Cachexia
  • Melanocortin-4 receptor
  • Pharmacokinetics
  • SAR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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