Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor
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Acknowledgment
The authors thank Dr. Daniel Marks of Oregon Health & Science University for his help in performing the mouse cachexia study.
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Treatment of Cachexia. Melanocortin and Ghrelin Interventions.
2013, Vitamins and HormonesCitation Excerpt :In humans, heterozygosity for a single, neutral mutation decreased cachexia frequency in nonleukemic cancer patients (22% vs. 0%, p < 0.05; DeBoer, 2010; Knoll et al., 2008), suggesting that melanocortin antagonism may assist in reversing cancer cachexia. As seen in Table 8.2, MC4R antagonism significantly increases food intake (Chen et al., 2008; Jiang et al., 2007; Joppa, Gogas, Foster, & Markison, 2007; Markison et al., 2005; Marks et al., 2001; Tran et al., 2007; Weyermann et al., 2009), TBM (Chen et al., 2008; Joppa et al., 2007; Markison et al., 2005; Marks et al., 2001; Vos et al., 2004; Weyermann et al., 2009), LBM (Jiang et al., 2007; Joppa et al., 2007; Markison et al., 2005; Nicholson et al., 2006; Tran et al., 2007; Weyermann et al., 2009), and FM (Joppa et al., 2007; Markison et al., 2005; Weyermann et al., 2009) versus vehicle-treated controls. In one study, total food consumption did not change in tumor-bearing mice receiving a small molecule melanocortin antagonist versus vehicle controls, while LBM, FM, and light-phase food intake significantly increased (Nicholson et al., 2006).
Automated generation of turn mimetics: Proof of concept study for the MC4 receptor
2012, Bioorganic and Medicinal ChemistryCitation Excerpt :This receptor is associated with weight homeostatis11 and ligands for this receptor, both agonists and antagonists, are being pursued by a number of pharmaceutical companies for this purpose and other indications.12 Different kinds of MC4 inhibitors have been tested at Neurocrine Biosciences13–15 and the de novo design of turn mimetics was viewed as a novel way to generate ideas for alternative starting points. One natural peptide ligand of this receptor is α-MSH16 (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2).
Update on melanocortin interventions for cachexia: Progress toward clinical application
2010, NutritionCitation Excerpt :These experiments were then followed by treatment with small-molecule inhibitors, which themselves were administered by ICV catheters [3,40–42]. Perhaps the greatest advance in the field of melanocortin antagonism from a clinical perspective has been the introduction of peripherally administrated compounds with efficacy in cachexia treatment (Table 1) [8,43–49]. Over the previous 5 y, the field has rapidly evolved to the point were at least seven small-molecule inhibitors have been reported in the scientific literature to have efficacy after peripheral administration in a variety of animal models of disease-associated cachexia.
Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists
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