The discovery and optimization of pyrimidinone-containing MCH R1 antagonists

Hertzog, Donald L.; Al-Barazanji, K. A.; Bigham, Eric C.; Bishop, Michael J.; Britt, Christy S.; Carlton, David; Cooper, Joel P.; Daniels, Alex; Garrido, Dulce; Goetz, Aaron S.; Grizzle, Mary K.; Guo, Yu; Handlon, Anthony L.; Ignar, Diane M.; Morgan, Ronda O.; Peat, Andrew J.; Tavares, Francis X.; Zhou, Hongmin

doi:10.1016/j.bmcl.2006.07.008

Cited by 43 publications

(21 citation statements)

References 12 publications

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“…GW803430 is a potent, non-peptide, brain penetrant MCH1-R antagonist (Hertzog et al 2006). It has previously been shown to decrease food intake and weight in mice, an effect that was absent in animals with disruption of the MCH1-R gene and thus receptor-specific.…”

Section: Introductionmentioning

confidence: 99%

Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats

et al. 2010

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“…GW803430 is a potent and selective non-peptide MCHR1 antagonist (22) that has been suggested to have weight-reducing effects (23). To examine exactly how GW803430 affected energy balance and glucose homeostasis, we evaluated energy budgets at early (day 4-6) and late (day 22-24) stages of a 30-day oral treatment, compared to a control group receiving only vehicle.…”

Section: Introductionmentioning

confidence: 99%

Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet‐induced obese mice

Zhang

Sinclair

Selman

et al. 2013

Obesity

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Objective: The melanin-concentrating hormone (MCH) is a centrally acting peptide implicated in the regulation of energy homeostasis and body weight, although its role in glucose homeostasis is uncertain. Our objective was to determine effects of MCHR1 antagonism on energy budgets and glucose homeostasis in mice. Methods: Effects of chronic oral administration of a specific MCHR1 antagonist (GW803430) on energy budgets and glucose homeostasis in diet-induced obese (DIO) C57BL/6J mice were examined. Results: Oral administration of GW803430 for 30 days reduced food intake, body weight, and body fat. Circulating leptin and triglycerides were reduced but insulin and nonesterified fatty acids were unaffected. Despite weight loss there was no improvement in glucose homeostasis (insulin levels and intraperitoneal glucose tolerance tests). On day 4-6, mice receiving MCHR1 antagonist exhibited decreased metabolisable energy intake and increased daily energy expenditure. However these effects had disappeared by day 22-24. Physical activity during the dark phase was increased by MCHR1 antagonist treatment throughout the 30-day treatment. Conclusions: GW803430 produced a persistent anti-obesity effect due to both a decrease in energy intake and an increase in energy expenditure via physical activity but did not improve glucose homeostasis.

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“…Multiple MCHR1 antagonists have also shown dose-dependent and sustained efficacy in chronic models of obesity (Kym et al, 2005; Souers et al, 2005a,b, 2007; Vasudevan et al, 2005a,b; Carpenter et al, 2006; Hertzog et al, 2006; Tavares et al, 2006a,b; Mendez-Andino and Wos, 2007; Mendez-Andino et al, 2007; Gehlert et al, 2009; Ito et al, 2009; Semple et al, 2009; Suzuki et al, 2009; Hadden et al, 2010; Mihalic et al, 2012; Sasmal et al, 2012a,b). At the highest dose tested in DIO mice, ranging from 10 to 100 mpk, weight loss ranged from 5% at 5 days to 33% at 238 days (Ito et al, 2009; Mihalic et al, 2012).…”

Section: Pharmacologic Studies Confirm a Role For Mch In Energy Homeomentioning

confidence: 99%

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

MacNeil¹

2013

Front. Endocrinol.

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Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet-induced obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of obesity, with an ultimate goal to identify novel anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting body-weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long-term efficacy and safety studies.

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The discovery and optimization of pyrimidinone-containing MCH R1 antagonists

Cited by 43 publications

References 12 publications

Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats

Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats

Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet‐induced obese mice

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

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