Setmelanotide (RM-493)
(Synonyms: 司美诺肽) 目录号 : GC30372
Setmelanotide (RM-493, BIM-22493, CAM 4072) is a cyclic peptide full agonist of melanocortin-4 receptor (MC4R) with an EC50 of 0.27 nM and a Ki of 2.1 nM.
Cas No.:920014-72-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Cell membranes are prepared from CHO-K1 cells stably expressing the human melanocortin receptor subtypes (MC1R, MC3R, MC4R and MC5R). They are incubated at 1-10 μg protein/well in 50 mM Tris-HCl, pH 7.4, containing 0.2% BSA, 5 mM MgCl2, 1 mM CaCl2 and 0.1 mg/mL bacitracin, with increasing concentrations of setmelanotide and 0.1-0.3 nM [125I]-NDP-α-MSH for 90-120 min at 37°C, depending on the receptor subtype. Bound from free [125I]-NDP-α-MSH is separated by filtration through GF/C glass fiber filters presoaked with 0.1 % (w/v) PEI. Filters are washed three times with 50 mM Tris-HCl, pH 7.4, at 0-4°C and assayed for radioactivity using Perkin Elmer Topcount scintillation counter[1]. |
Animal experiment: | Mice: Mice are weighed. Baseline blood glucose is measured and 2 g/kg body weight of D-glucose injected by i.p. BIM-22493 is administered chronically at a dose of 300 nmol/kg/day for 14 days by sc. osmotic pump. Controls are administered with 0.9% saline during the same period. Blood glucose is measured at 15, 30, 60, and 120 minutes post injection[1]. |
References: [1]. Kumar KG, et al. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900. | |
Setmelanotide (RM-493, BIM-22493, CAM 4072) is a cyclic peptide full agonist of melanocortin-4 receptor (MC4R) with an EC50 of 0.27 nM and a Ki of 2.1 nM.
Setmelanotide decreases TNF-α/IFN-γ-induced chemokine expression in astrocytes and increases IL-6 and IL-11 mRNA and protein secretion via MC4R. Setmelanotide Induces CREB phosphorylation in astrocytes and setmelanotide treated astrocytes secrete factors that are able to modulate macrophage polarization into an anti-inflammatory phenotype.[2]
RM-493 and liraglutide co-treatment enhances weight loss in DIO mice and hypothalamic Glp-1r expression is higher in mice treated with the combination therapy after both acute and chronic treatment. Adjunctive administration of RM-493 and liraglutide improves glucose tolerance and insulin sensitivity, lowers fasting levels of glucose and insulin and decreases cholesterol levels beyond what can be achieved with the corresponding mono-therapies.[3]
[1] Kong Y Chen, et al. J Clin Endocrinol Metab. 2015 Apr;100(4):1639-45. [2] Alwin Kamermans, et al. Front Immunol. 2019 Oct 4;10:2312. [3] Christoffer Clemmensen, et al. EMBO Mol Med. 2015 Mar; 7(3): 288–298.
| Cas No. | 920014-72-8 | SDF | |
| 别名 | 司美诺肽 | ||
| Canonical SMILES | O=C(N[C@@H](CSSC[C@](C(N[C@@H]1C)=O)([H])NC([C@@H](NC(C)=O)CCCNC(N)=N)=O)C(N)=O)[C@@H](NC([C@@H](NC([C@@](NC([C@@H](NC1=O)CC2=CN=CN2)=O)([H])CC3=CC=CC=C3)=O)CCCNC(N)=N)=O)CC4=CNC5=CC=CC=C45 | ||
| 分子式 | C49H68N18O9S2 | 分子量 | 1117.31 |
| 溶解度 | Water : ≥ 24 mg/mL (21.48 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.895 mL | 4.475 mL | 8.9501 mL |
| 5 mM | 0.179 mL | 0.895 mL | 1.79 mL |
| 10 mM | 0.0895 mL | 0.4475 mL | 0.895 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Setmelanotide: First Approval
Setmelanotide (IMCIVREE?, Rhythm Pharmaceuticals) is a melanocortin-4 (MC4) receptor agonist developed for the treatment of obesity arising from proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The drug has received its first approval in the USA for chronic weight management in patients 6 years and older with obesity caused by POMC, PCSK1 and LEPR deficiency and has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4 receptor pathway. Setmelanotide is also being developed in other rare genetic disorders associated with obesity including Bardet-Biedl Syndrome, Alstr?m Syndrome, POMC and other MC4R pathway heterozygous deficiency obesities, and POMC epigenetic disorders. This article summarizes the milestones in the development of setmelanotide leading to this first approval for obesity caused by POMC, PCSK1 and LEPR deficiency.
Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?
There is a new generation of antiobesity drugs in development or just arriving on the scene. First, setmelanotide has been approved for three of the ultrarare genetic conditions that cause obesity-pro-opiomelanocortin deficiency, proprotein convertase subtilisin and kexin type 1 (an important enzyme in the melanocortin pathway) and leptin receptor deficiency. Setmelanotide marks the first in a personalized medicine approach to obesity. Second, semaglutide 2.4 mg once weekly has been submitted to regulators in the United States and the European Union for approval for patients with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one weight related comorbidity. This drug has been studied in five phase 3 clinical trials, four discussed herein: semaglutide produces roughly twice as much weight loss as we have seen in older antiobesity medications. Semaglutide is already in use for treatment of diabetes and, as a glucagon-like peptide 1 (GLP-1) receptor analog, is part of a class of drugs used widely in diabetes. Tirzepatide, a glucose-insulin peptide and GLP-1 dual agonist is in phase 3 study for obesity management, and bimagrumab is a new agent in phase 2 with a unique mechanism of action; they are generating much interest. The purpose of this narrative review is lay the groundwork for a discussion of the clinical impact of these new medications on the clinical practice of obesity. Further, these developments shall be used to launch a speculation of what is likely to be their impact on the future of obesity pharmacotherapy.
Progress in Pharmacotherapy for Obesity
Drugs for Treating Obesity
Older medications approved for chronic weight management (orlistat, naltrexone/bupropion, liraglutide 3 mg and, in the USA, phentermine/topiramate) have not been widely adopted by health care providers. Those medications produce only modest additional weight loss when used to augment lifestyle intervention. However, semaglutide 2.4 mg weekly has recently emerged and produces much more weight loss - on average 15% weight loss at 1 year. Semaglutide's enhanced efficacy and that its class (GLP-1 receptor analogs) is well-known may result in more clinicians adopting pharmacotherapy. Furthermore, the first dedicated cardiovascular outcome trial powered for superiority testing an anti-obesity medication (SELECT) is underway with semaglutide 2.4 mg. A positive outcome will further promote the concept that weight management should be a primary target for cardiometabolic disease control. In phase 3, tirzepatide and cagrilintide/semaglutide combination are showing promise for even greater weight loss efficacy. Another recently approved medication takes a personalized medicine approach; setmelanotide is approved as a therapy for those with some of the ultra-rare genetic diseases characterized by severe, early onset obesity. This chapter reviews the currently available and anticipated medications for chronic weight management as well as those approved for the genetic and syndromic obesities.
The melanocortin pathway and energy homeostasis: From discovery to obesity therapy
Background: Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.
Scope of review: Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.
Major conclusions: Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.