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

Bioorganic & Medicinal Chemistry
Chen ChenDaniel L Marks

Abstract

A series of 2-piperazine-alpha-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 1mg/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 effect...Continue Reading

References

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Citations

Aug 25, 2010·Current Opinion in Supportive and Palliative Care·Stephanie M Krasnow, Daniel L Marks
Feb 18, 2010·Expert Opinion on Drug Discovery·Mark Daniel Deboer
Apr 9, 2015·Pharmaceutical Patent Analyst·Esther C Y Lee, Philip A Carpino
Feb 7, 2018·Nature Reviews. Clinical Oncology·Vickie E Baracos
Dec 18, 2015·Journal of Cachexia, Sarcopenia and Muscle·Chukwuemeka Charles Ezeoke, John E Morley
Apr 28, 2010·Chemical Reviews·MaryAnn T RobakJonathan A Ellman

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