MCH-R1 antagonists: what is keeping most research programs away from the clinic?

Méndez‐Andino, José; Wos, John A.

doi:10.1016/j.drudis.2007.08.010

Cited by 56 publications

(35 citation statements)

References 56 publications

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“…The pharmaceutical industry is currently very interested in targeting the MCH system as a therapeutic in the treatment of obesity because of its regulatory role in feeding behaviours and energy expenditure, though the development of such a compound has not been without challenges (Mendez-Andino & Wos 2007, Hogberg et al 2012. Of particular relevance are studies that report that the deletion of either the Pmch gene or MCH receptor (Mchr1) results in resistance to diet-induced obesity , Kokkotou et al 2005, Mashiko et al 2005.…”

Section: Part 1: Mch Appetite Regulation and Energy Expenditurementioning

confidence: 99%

The roles of melanin-concentrating hormone in energy balance and reproductive function: are they connected?

Naufahu¹,

Cunliffe²,

Murray³

2013

Reproduction

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Melanin-concentrating hormone (MCH) is an anabolic neuropeptide with multiple and diverse physiological functions including a key role in energy homoeostasis. Rodent studies have shown that the ablation of functional MCH results in a lean phenotype, increased energy expenditure and resistance to diet-induced obesity. These findings have generated interest among pharmaceutical companies vigilant for potential anti-obesity agents. Nutritional status affects reproductive physiology and behaviours, thereby optimising reproductive success and the ability to meet energetic demands. This complex control system entails the integration of direct or indirect peripheral stimuli with central effector systems and involves numerous mediators. A role for MCH in the reproductive axis has emerged, giving rise to the premise that MCH may serve as an integratory mediator between those discrete systems that regulate energy balance and reproductive function. Hence, this review focuses on published evidence concerning i) the role of MCH in energy homoeostasis and ii) the regulatory role of MCH in the reproductive axis. The question as to whether the MCH system mediates the integration of energy homoeostasis with the neuroendocrine reproductive axis and, if so, by what means has received limited coverage in the literature; evidence to date and current theories are summarised herein.Reproduction (2013) 146 R141-R150

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Section: Part 1: Mch Appetite Regulation and Energy Expenditurementioning

confidence: 99%

The roles of melanin-concentrating hormone in energy balance and reproductive function: are they connected?

Naufahu¹,

Cunliffe²,

Murray³

2013

Reproduction

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“…Among these GW 856464 [211], AMG076 [212] and NGD-4715 [213] achieved phase 1 clinical investigations. Trials to optimize quinazolines [214][215][216][217][218][219], as (40) (Figure 9(a)), revealed GW 803430 (GW3430; [214]), ATC0175 and ATC0065 [215] which were shown efficacious in rodent depression models [197].…”

Section: Non-peptide Ligands Of Mch-receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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“…One of the main reasons for the lack of clinical development has been the propensity for selective agents to have significant cardiovascular liabilities. Many of the early compounds displayed significant human ether-a-go-go-related gene-binding activity and drug-induced QTc prolongation [52].…”

Section: Melanin Concentrating Hormone Antagonistsmentioning

confidence: 99%

“…These so-called 'leptinsensitive' neurons express significant amounts of MCH. MCH has been identified as an orexigenic peptide that exerts an effect on food intake and body weight regulation [51,52]. MCH is a cyclic 19 amino acid neuropeptide expressed in the lateral hypothalamus in response to both energy restriction and leptin deficiency.…”

Section: Melanin Concentrating Hormone Antagonistsmentioning

confidence: 99%

New central targets for the treatment of obesity

Sargent

Moore

2009

Brit J Clinical Pharma

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The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation 'New central targets for the treatment of obesity ' (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008). Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non-specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5-HT2c and 5-HT6). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH1 receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co-morbid conditions such as diabetes and cardiovascular disorders. The obesity problemObesity is a major global health problem and rates of obesity [body mass index (BMI) >30 kg m -2 ] have risen steadily year on year. Recent figures show an incidence of obesity of more than 1 in 4 in many parts of the USA [1]. These high rates are similar in other developed countries and the incidence of weight gain is increasing in less developed regions. Obesity is not just a cosmetic or lifestyle illness but leads to many life-threatening health complications. As the BMI increases the incidence of metabolic disorders (Type 2 diabetes), hypertension, cancer and musculoskeletal problems increases [1][2][3]. In 1999, Calle et al. reported mortality rates for all causes doubled when the BMI increased from 25 to >35 [4].The annual direct healthcare costs associated with obesity in the USA are in excess of $93 billion [5]. Particularly worrying is the fact that the incidence of obesity in children and young adults is on the increase, with some reports suggesting that up to 25% of children may be obese. The long-term health implications of these findings are far reaching and suggest that for the first time intergenerational increase in life expectancy will not occur and these children will have a shorter life span than their parents because of health complications associated with weight gain [6] (Figure 1).Obesity occurs when the balance between energy input (food intake) and energy expenditure (exercise, activity) is disrupted, i.e. more food is consumed than utilized, leading to excess fat stores being laid down. Although for some people a calorie-restricted diet and exercise can lead to a reduction in weight gain, for many peop...

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MCH-R1 antagonists: what is keeping most research programs away from the clinic?

Cited by 56 publications

References 56 publications

The roles of melanin-concentrating hormone in energy balance and reproductive function: are they connected?

The roles of melanin-concentrating hormone in energy balance and reproductive function: are they connected?

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

New central targets for the treatment of obesity

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