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

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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
Volume50
Issue number25
DOIs
StatePublished - Dec 15 2007

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Receptor, Melanocortin, Type 4
Pharmacokinetics
Cachexia
Bearings (structural)
Tumors
Rodentia
Brain
Neoplasms
Eating
Pharmacology
Derivatives
In Vitro Techniques
phenylpiperazine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor. / Tran, Joe A.; Jiang, Wanlong; Tucci, Fabio C.; Fleck, Beth A.; Wen, Jenny; Sai, Yang; Madan, Ajay; Ta, Kung Chen; Markison, Stacy; Foster, Alan C.; Hoare, Sam R.; Marks, Daniel; Harman, John; Chen, Caroline W.; Arellano, Melissa; Marinkovic, Dragan; Bozigian, Haig; Saunders, John; Chen, Chen.

In: Journal of Medicinal Chemistry, Vol. 50, No. 25, 15.12.2007, p. 6356-6366.

Research output: Contribution to journalArticle

Tran, JA, Jiang, W, Tucci, FC, Fleck, BA, Wen, J, Sai, Y, Madan, A, Ta, KC, Markison, S, Foster, AC, Hoare, SR, Marks, D, Harman, J, Chen, CW, Arellano, M, Marinkovic, D, Bozigian, H, Saunders, J & Chen, C 2007, 'Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor', Journal of Medicinal Chemistry, vol. 50, no. 25, pp. 6356-6366. https://doi.org/10.1021/jm701137s
Tran, Joe A. ; Jiang, Wanlong ; Tucci, Fabio C. ; Fleck, Beth A. ; Wen, Jenny ; Sai, Yang ; Madan, Ajay ; Ta, Kung Chen ; Markison, Stacy ; Foster, Alan C. ; Hoare, Sam R. ; Marks, Daniel ; Harman, John ; Chen, Caroline W. ; Arellano, Melissa ; Marinkovic, Dragan ; Bozigian, Haig ; Saunders, John ; Chen, Chen. / Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 25. pp. 6356-6366.
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