Discovery of Tyrosine-Based Potent and Selective Melanocortin-1 Receptor Small-Molecule Agonists with Anti-inflammatory Properties

Herpin, Timothy F.; Yu, Ga-Er; Carlson, Kenneth E.; Morton, George; Wu, Ximao; Kang, Liya; Tuerdi, Huji; Khanna, Ashish K.; Tokarski, John S.; Lawrence, R. Michael; Macor, John E.

doi:10.1021/jm025600i

Cited by 57 publications

(53 citation statements)

References 37 publications

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“…Our laboratory recently reported the discovery of a potent and selective MC-1R agonist BMS-470539 [27]. This current study further characterizes this compound and describes its pharmacokinetic and pharmacodynamic properties along with its effects on LPS-induced cytokine production, LPS-induced leukocyte infiltration into the lung, and delayed-type hypersensitivity (DTH).…”

Section: Introductionmentioning

confidence: 89%

A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice

Kang

McIntyre

Gillooly

et al. 2006

Journal of Leukocyte Biology

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It is well established that melanocortins are peptides that have potent anti-inflammatory activity. Recent research has focused on understanding which of the known melanocortin receptors mediates the anti-inflammatory actions of the melanocortins. The aim of this study was to assess the anti-inflammatory activity of a synthetic MC-1R agonist. BMS-470539 is a potent, selective, full agonist of human and murine MC-1R with EC(50) values in a cAMP accumulation assay of 16.8 and 11.6 nM, respectively. BMS-470539 dose-dependently inhibited TNF-alpha-induced activation of a NF-kappaB transcriptional reporter in human melanoma cells, which endogenously express MC-1R. In vivo studies with BMS-470539 demonstrated that subcutaneous administration of BMS-470539 resulted in a dose-dependent inhibition of LPS-induced TNF-alpha production in BALB/c mice. In this model, the compound had an ED(50) of approximately 10 micromol/kg and a pharmacodynamic half-life of approximately 8 h. Pharmacokinetic analysis of the compound indicated that the compound had a t(1/2) of 1.7 h. In a model of lung inflammation, administration of 15 micromol/kg BMS-470539 resulted in a 45% reduction in LPS-induced leukocyte infiltration (an infiltrate comprised primarily of neutrophils). The compound was also effective in a model of delayed-type hypersensitivity, reducing paw swelling by 59%, comparable with that seen with 5 mg/kg dexamethasone. These studies demonstrate that a selective small molecule agonist of the melanocortin-1 receptor is a potent anti-inflammatory agent in vivo and provides compelling evidence for the involvement of this receptor in the modulation of inflammation.

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Section: Introductionmentioning

confidence: 89%

A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice

Kang

McIntyre

Gillooly

et al. 2006

Journal of Leukocyte Biology

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“…Peptidomimetic agents targeted to melanocortin receptor subtypes could be more stable and provide sustained blood concentrations. Design and synthesis of such molecules is already in progress, and they could form the basis for novel therapeutic approaches Hruby, 2001;Fotsch et al, 2003;Herpin et al, 2003;Mazur et al, 2003;Wikberg et al, 2003).…”

Section: Advantages Over Currently Used Antiinflammatory Drugs Andmentioning

confidence: 99%

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

et al. 2004

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“…8,9 Conversely, selective MC1-R and MC3-R agonists exert anti-inflammatory actions and put in motion proresolving processes. [10][11][12][13] Recent data also indicate that MC1-R activation in an inflamed vasculature can inhibit cell adhesion and migration by acting on the adherent leukocytes and reduce the levels of a variety of chemokines, which are known to contribute to the pathogenesis of atherosclerosis. However, these findings have been exclusively derived from acute experiments such as vascular and cardiac ischemia/reperfusion models, whereas the potential of MC1-R and MC3-R activation in chronic inflammatory conditions such as atherosclerosis remains unexplored.…”

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confidence: 99%

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

Rinne

Silvola

Hellberg

et al. 2014

ATVB

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A therosclerosis is a chronic inflammatory disease causing progressive lesion formation and luminal narrowing of arteries. The underlying pathology is initiated by endothelial dysfunction and structural alterations after an imbalanced lipid metabolism and trapping of low-density lipoprotein (LDL) particles in the intima of arteries.1,2 Subsequently, intimal lipid accumulation triggers the release of various chemokines by activated endothelial cells, inducing a multiphase cascade of leukocyte infiltration and inflammatory responses in the arterial walls. As the knowledge of these inflammatory pathways has been growing during the past years, it has also uncovered new druggable targets that could complement the current treatment options, which do not directly interfere with the central inflammatory mechanisms driving atheroprogression. One endogenous pathway that has gained increasing attention for its wide-ranging and potent actions in suppressing maladaptive inflammatory responses is the melanocortin system consisting of melanocortin peptides and their cellular receptors. 3,4 However, the role of melanocortin signaling and its promise as a therapeutic target in atherosclerosis remain fully unexplored.Melanocortins are a family of peptides that are proteolytically cleaved from the common precursor molecule pro-opiomelanocortin. These peptides include melanocyte-stimulating hormones (α-, β-, and γ-MSH) and adrenocorticotropic hormone. They regulate important physiological functions by acting via G-protein-coupled melanocortin receptors (MC-Rs), named from MC1-R to MC5-R. 5,6 Our recent findings indicate that α-MSH serves as a protective regulator in the vasculature by enhancing endothelium-dependent control of blood vessel tone. 7 Mechanistically, α-MSH was shown to augment vascular nitric oxide (NO) availability by activating MC1-R in the endothelium. Besides promoting endothelial function, mounting evidence indicates that α-MSH, through the activation of © 2014 American Heart Association, Inc. Objective-Melanocortin peptides have been shown to elicit anti-inflammatory actions and to promote vascular endothelial function by activating type 1 and 3 melanocortin receptors. Here, we addressed whether these favorable properties of melanocortins could reduce atherosclerotic plaque inflammation and improve vasoreactivity in atherosclerotic mice. Approach and Results-Low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 were fed a high-fat diet for 8 or 16 weeks and treated with either vehicle or a stable melanocortin analog, melanotan II (MT-II, 0.3 mg/kg per day, 4 weeks). We determined plaque uptake of fluorine-18-labeled fluorodeoxyglucose as a surrogate marker for atherosclerotic plaque inflammation and vascular function of the aorta by ex vivo analyses. MT-II had no effect on body weight or composition, or plasma cholesterol levels in atherosclerotic mice. Without attenuating atherosclerotic lesion size or lesional macrophage accumulation, MT-II treatment reduced fluorine-18-labeled...

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Discovery of Tyrosine-Based Potent and Selective Melanocortin-1 Receptor Small-Molecule Agonists with Anti-inflammatory Properties

Cited by 57 publications

References 37 publications

A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice

A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

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