Identification of 2-{2-[2-(5-Bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl}-4,5-dihydro-1<i>H</i>-imidazole (ML00253764), a Small Molecule Melanocortin 4 Receptor Antagonist That Effectively Reduces Tumor-Induced Weight Loss in a Mouse Model

Vos, Tricia J.; Caracoti, Andrei; Jennifer, L; Dai, Mingshi; Farrer, Cheryl A; Forsyth, Nancy; Drabic, Stacey; Horlick, Robert A.; Lamppu, Diana; Yowe, David; Balani, Suresh K.; Li, Ping; Zeng, Hang; Joseph, Ingrid B.J.; Rodrı́guez, Luis E.; Maguire, Martin P.; Patane, Michael A.; Claiborne, Christopher F.

doi:10.1021/jm034244g

Cited by 101 publications

(55 citation statements)

References 17 publications

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“…The results reported from this study are well in accordance with previous studies describing robust orexigenic effects and showing that endogenous peptidic or small molecule MC4R antagonists enhance food intake in healthy animals [44,50]. Besides the experiments using SNT2007707 and SNT207858 in C26 adenocarcinoma mice performed by Weyermann [45], a number of other compounds with MC4R antagonist effects were investigated elsewhere -Chen et al [52] reported on a new compound from piperazine family, the name of which is yet to be attributed, Vos et al [53] investigated effects of ML00253764 in C26 adenocarcinoma mice, Nicholson et al [44] investigated ML00253764 in Lewis Lung carcinoma mice. Cheung et al [54] investigated effects of a MC4R antagonist called NBI-12i in rodent models of cachexia with 5/6 nephrectomy where 3 mg/kg of NBI-12i or saline was given to subtotally nephrectomized or sham-operated mice intraperitoneally, twice per day, for a period of 14 days.…”

Section: Currently Available Small-molecule Inhibitors Of MC Pathwaysupporting

confidence: 90%

Melanocortin system in cancer-related cachexia

et al. 2011

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AbstractThe melanocortin system plays a pivotal role in the regulation of appetite and energy balance. It was recognized to play an important role in the development of cancer-related cachexia, a debilitating condition characterized by progressive body wasting associated with anorexia, increased resting energy expediture and loss of fat as well as lean body mass that cannot be simply prevented or treated by adequate nutritional support.The recent advances in understanding of mechanisms underlying cancer-related cachexia led to consequent recognition of the melanocortin system as an important potential therapeutic target. Several molecules have been made available for animal experiments, including those with oral bioavailability, that act at various checkpoints of the melanocortin system and that might confer singificant benefits for the patients suffering from cancer-related cachexia. The application of melanocortin 4 receptor antagonists/agouti-related peptide agonists has been however restricted to animal models and more pharmacological data will be necessary to progress to clinical trials on humans. Still, pharmacological targeting of the melanocortin system seem to represent an elegant and promising way of treatment of cancer-related cachexia.

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Section: Currently Available Small-molecule Inhibitors Of MC Pathwaysupporting

confidence: 90%

Melanocortin system in cancer-related cachexia

et al. 2011

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“…In the present study, we have investigated the effect of chronic peripheral administration of a MC4-R ligand, ML00253764 (Vos et al, 2004), in a murine model of cancer cachexia. This compound has been previously shown to increase body weight in CT-26 tumor-bearing BALB/c mice (Vos et al, 2004), and in the present study, we have extended these findings by investigating the in vitro characteristics of this compound and its in vivo effects on food intake and body composition in C57BL6 mice bearing s.c. Lewis lung carcinoma tumors.…”

mentioning

confidence: 99%

Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice

Nicholson

Kohler²,

Schaerer³

et al. 2006

J Pharmacol Exp Ther

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Cachexia affects many different chronically ill patient populations, including those with cancer. It results in loss of body weight, particularly of lean body mass (LBM), and is estimated to be responsible for over 20% of all cancer-related deaths. Currently, available drugs are ineffective, and new therapies are urgently needed. Melanocortin 4-receptor (MC4-R) blockade has been shown recently to be effective in preventing cancer cachexia in rodent models. In the present study, we have tested mulation (maximal reduction of Ϫ20%) indicative of inverse agonist activity. ML00253764 was administered twice daily (15 mg/kg s.c.) for 13 days to C57BL6 mice bearing s.c. Lewis lung carcinoma tumors. Food intake and body weight were measured, and body composition was assessed using magnetic resonance relaxometry. ML00253764 stimulated light-phase food intake relative to vehicle-treated controls (p Ͻ 0.05), although no effect was observed on 24-h food intake. During the 21 days of the experiment, the LBM of tumor vehicle-treated mice decreased (p Ͻ 0.05). In contrast, the tumor-bearing mice treated with ML00253764 maintained their LBM. These data support the view that MC4-R blockade may be a suitable approach for the treatment of cancer cachexia and that MC4-R inverse agonists may have potential as drug candidates.

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“…However, they are being explored for other conditions such as sexual dysfunction [64]. Melanocortin antagonists are also being evaluated for the treatment of cachexia [65,66]. …”

Section: Novel Targets and Drug Candidatesmentioning

confidence: 99%

Obesity Pharmacotherapy: Current Perspectives and Future Directions

Misra

2013

Current Cardiology Reviews

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The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis

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Identification of 2-{2-[2-(5-Bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazole (ML00253764), a Small Molecule Melanocortin 4 Receptor Antagonist That Effectively Reduces Tumor-Induced Weight Loss in a Mouse Model

Cited by 101 publications

References 17 publications

Melanocortin system in cancer-related cachexia

Melanocortin system in cancer-related cachexia

Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice

Obesity Pharmacotherapy: Current Perspectives and Future Directions

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