BMS 470539 dihydrochloride

BMS 470539 dihydrochloride is a potent and selective melanocortin-1 (MC1) receptor agonist with IC50 of 120 nM [1].
The melanocortin-1 receptor (MC-1R) is a G protein-coupled receptor involved in blocking inflammation and augmenting skin pigmentation [1].
In human melanoma cells, which endogenously express MC-1R, BMS-470539 inhibited TNF- -induced activation of a NF-κB transcriptional reporter in a dose-dependent way.
In a murine LPS (lipopolysaccharide) induced cytokine accumulation model, BMS 470539 dihydrochloride reduced TNF-α levels by 65% and 82% at 11umol/kg and 33umol/kg respectively in a dose-dependent way [1]. In a murine lung inflammation model, BMS 470539 (15umol/kg) reduced LPS-induced leukocyte infiltration (comprised primarily of neutrophils) by 45%. In a delayed-type hypersensitivity model, BMS 470539 reduced paw swelling by 59% [2]. In mice with IR, BMS 470539 (doses of 6.16 and 18.47 mg/kg) significantly inhibited leucocyte adhesion and emigration in a dose-dependent way. In the cremasteric microcirculation inflamed by platelet-activating factor, BMS-470539 inhibited cell emigration, but did not affect cell adhesion [3].
References:
[1]. Herpin TF, Yu G, Carlson KE, et al. Discovery of tyrosine-based potent and selective melanocortin-1 receptor small-molecule agonists with anti-inflammatory properties. J Med Chem, 2003, 46(7): 1123-1126.
[2]. Kang L, McIntyre KW, Gillooly KM, et al. A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice. J Leukoc Biol, 2006, 80(4): 897-904.
[3]. Leoni G, Voisin MB, Carlson K, et al. The melanocortin MC(1) receptor agonist BMS-470539 inhibits leucocyte trafficking in the inflamed vasculature. Br J Pharmacol, 2010, 160(1): 171-180.

The melanocortin MC(1) receptor agonist BMS-470539 inhibits leucocyte trafficking in the inflamed vasculature.[Pubmed:20331604]

Br J Pharmacol. 2010 May;160(1):171-80.

BACKGROUND AND PURPOSE: Over three decades of research evaluating the biology of melanocortin (MC) hormones and synthetic peptides, activation of the MC type 1 (MC(1)) receptor has been identified as a viable target for the development of novel anti-inflammatory therapeutic agents. Here, we have tested a recently described selective agonist of MC(1) receptors, BMS-470539, on leucocyte/post-capillary venule interactions in murine microvascular beds. EXPERIMENTAL APPROACH: Intravital microscopy of two murine microcirculations were utilized, applying two distinct modes of promoting inflammation. The specificity of the effects of BMS-470539 was assessed using mice bearing mutant inactive MC(1) receptors (the recessive yellow e/e colony). KEY RESULTS: BMS-470539, given before an ischaemia-reperfusion protocol, inhibited cell adhesion and emigration with no effect on cell rolling, as assessed 90 min into the reperfusion phase. These properties were paralleled by inhibition of tissue expression of both CXCL1 and CCL2. Confocal investigations of inflamed post-capillary venules revealed immunostaining for MC(1) receptors on adherent and emigrated leucocytes. Congruently, the anti-inflammatory properties of BMS-470539 were lost in mesenteries of mice bearing the inactive mutant MC(1) receptors. Therapeutic administration of BMS-470539 stopped cell emigration, but did not affect cell adhesion in the cremasteric microcirculation inflamed by superfusion with platelet-activating factor. CONCLUSIONS AND IMPLICATIONS: Activation of MC(1) receptors inhibited leucocyte adhesion and emigration. Development of new chemical entities directed at MC(1) receptors could be a viable approach in the development of novel anti-inflammatory therapeutic agents with potential application to post-ischaemic conditions.

A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice.[Pubmed:16888084]

J Leukoc Biol. 2006 Oct;80(4):897-904.

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.

Discovery of tyrosine-based potent and selective melanocortin-1 receptor small-molecule agonists with anti-inflammatory properties.[Pubmed:12646021]

J Med Chem. 2003 Mar 27;46(7):1123-6.

The melanocortin-1 receptor (MC-1R) is a G-protein-coupled receptor involved in inflammation and skin pigmentation. Compound 2 is the first highly potent and selective MC-1R small-molecule agonist reported. Compound 2 showed efficacy in an acute model of inflammation, which has demonstrated the role of MC-1R in modulation of inflammation.