1.54±0.1 g/cm3(Predicted)
HDHDTKMUACZDAA-PHNIDTBTSA-N
1S/C49H68N18O9S2/c1-26-41(70)63-37(20-30-22-55-25-59-30)46(75)64-35(18-28-10-4-3-5-11-28)44(73)62-34(15-9-17-57-49(53)54)43(72)65-36(19-29-21-58-32-13-7-6-12-31(29)32)45(74)66-38(40(50)69)23-77-78-24-39(47(76)60-26)67-42(71)33(61-27(2)68)14-8-16-56-48(51)52/h3-7,10-13,21-22,25-26,33-39,58H,8-9,14-20,23-24H2,1-2H3,(H2,50,69)(H,55,59)(H,60,76)(H,61,68)(H,62,73)(H,63,70)(H,64,75)(H,65,72)(H,66,74)(H,67,71)(H4,51,52,56)(H4,53,54,57)/t26-,33+,34+,35-,36+,37+,38+,39+/m1/s1
CC1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)N1)NC(=O)C(CCCN=C(N)N)NC(=O)C)C(=O)N)CC2=CNC3=CC=CC=C32)CCCN=C(N)N)CC4=CC=CC=C4)CC5=CN=CN5
The melanocortin-4 receptor (MC4R) plays an important role in weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity. In this work, the authors measured cell surface expression and α-melanocyte stimulating hormone (α-MSH) or setmelanotide-induced cAMP responses, β-arrestin-2 recruitment, and ERK activation in cells expressing wild-type or variant MC4R. The efficacy of setmelanotide in MC4R-evoked signaling responses was similar to that of α-MSH (P > .05). However, setmelanotide was significantly 22-fold more potent than α-MSH in the cAMP response (EC 50 of 0.2 nM and 11.9 nM, respectively). Compared with α-MSH, setmelanotide was significantly more potent than α-MSH by 21- and 40-fold for β-arrestin-2 recruitment and ERK activation, respectively.
Effect of α-MSH and setmelanotide on efficacy (Emax) and potency (EC 50) of MC4R cAMP response (A), β-arrestin-2 recruitment (B), and ERK activation (C). The cAMP response is presented as Emax relative to WT MC4R upon α-MSH stimulation. Values represent mean ± SEM from 3 to 4 independent experiments performed in duplicate. Statistical analysis was performed using unpaired two-tailed t-test; confidence level = 95%; * P ≤ .05 and **P ≤ .001.
1. Rodríguez Rondón A V. MC4R variants modulate α-MSH and setmelanotide induced cellular signaling at multiple levels[J]. The Journal of Clinical Endocrinology & Metabolism, 2024: dgae210.
To date, existing multiple sclerosis (MS) treatment strategies have been ineffective in preventing or reversing progressive neurological deterioration, creating a significant and unmet medical need. One potential approach to combating MS may be to limit the deleterious effects of reactive astrocytes. One class of compounds that may exert beneficial effects through astrocytes are melanocortin receptor (MCR) agonists. In this article, the authors found that setmelanotide, a novel highly selective MC4R agonist, ameliorated the reactive phenotype of astrocytes in vitro and significantly induced interleukin-6 and -11 production. This may be achieved by enhanced phosphorylation of the cAMP response element binding protein (CREB). Notably, stimulation of human macrophages with astrocyte medium exposed to setmelanotide biases macrophages toward an anti-inflammatory phenotype.
Setmelanotide time-dependently induces CREB phosphorylation. Representative western blots of MC4R+ astrocytes treated with setmelanotide (10 μM), lysed at 15, 30, and 60 min after stimulation. α-Tubulin was used as a protein loading control for both pCREB and CREB. Quantification of CREB phosphorylation relative to total CREB revealed significantly increased phosphorylation of CREB after setmelanotide stimulation. n = 3 independent experiments. One-way ANOVA. *p < 0.05, **p < 0.01.
1. Kamermans A. Setmelanotide, a novel, selective melanocortin receptor-4 agonist exerts anti-inflammatory actions in astrocytes and promotes an anti-inflammatory macrophage phenotype[J]. Frontiers in immunology, 2019, 10: 2312.
Setmelanotide is a medication primarily used for treating certain rare genetic disorders related to obesity. It is an agonist of the melanocortin-4 receptor (MC4R), which plays a crucial role in regulating hunger and energy expenditure. By activating this receptor, Setmelanotide can help reduce hunger and promote weight loss in individuals with POMC deficiency. By specifically targeting the melanocortin-4 receptor pathway, it offers a tailored therapeutic approach that addresses the underlying causes of obesity in patients with POMC deficiency, LEPR deficiency, Bardet-Biedl Syndrome, and potentially other related conditions. Ongoing research is likely to expand its applications and further refine its use in clinical practice.
What is the EC50 value of Setmelanotide excited melanocortin 4 receptor?
The EC50 value of Setmelanotide excited melanocortin 4 receptor was 0.27 nM.
08/12/2018
What is the activity of Setmelanotide in vivo?
Treatment with setmelanotide results in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model.
21/11/2019
Which knockout mice does Setmelanotide work on?
Setmelanotide (6.4 µmol/animal) inhibits food intake in MC3R, but not MC4R, knockout mice.
24/8/2022
improve glucose homeostasis
In our experiment, Setmelanotide significantly improved glucose homeostasis.
25/1/2020
1. The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design Murray W Stewart,Joan C Han,Gregory Gordon,Guojun Yuan,Jack A Yanovski,Robert M Haws Contemp Clin Trials Commun . 2021 May 3;22:100780. doi: 10.1016/j.conctc.2021.100780. Background:A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier:NCT03746522).Methods:It was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m2(in those aged ≥16 years) or a weight >97th percentile (in those aged 6-15 years) are included. Participants are initially randomized in a 1:1 ratio to receive setmelanotide or placebo for 14 weeks (period 1). Following period 1, all participants receive 38 weeks of open-label treatment with setmelanotide (period 2). In each treatment period, setmelanotide is administered at 3 mg once a day following completion of dose escalation. The primary endpoint is the proportion of participants aged ≥12 years achieving a clinically meaningful reduction from baseline (≥10%) in body weight after ~52 weeks (eg, following period 2). Safety and tolerability are assessed by frequency of adverse events.Conclusions:This pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome.Submission category:Study Design, Statistical Design, Study Protocols.
2. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency Florence Marchelli,Shubh Sharma,I Sadaf Farooqi,Edson Mendes de Oliveira,Andrew Gottesdiener,Tinh-Hai Collet,Rohia Alili,Rebecca Bounds,Bart Henderson,Julia M Keogh,Roger D Cone,Jean-Michel Oppert,Dominique Pépin,Lex H T Van der Ploeg,Patrick Tounian,Stephen O'Rahilly,Christine Poitou-Bernert,Elizabeth Stoner,Elana Henning,Jean-Marc Lacorte,Cathy Folster,Jacek Mokrosinski,Keith Gottesdiener,Hillori Connors,Brandon L Panaro,Béatrice Dubern,Karine Clément,Johanne Le Beyec Mol Metab . 2017 Oct;6(10):1321-1329. doi: 10.1016/j.molmet.2017.06.015. Objective:Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.Methods:We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.Results:In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.Conclusions:Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.
3. Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide Christian M T Spahn,David Speck,Michal Szczepek,Heike Biebermann,Peter Kühnen,Jörg Bürger,Patrick Scheerer,Sarah Paisdzior,Brian K Kobilka,Peter W Hildebrand,Daniel Hilger,Tarek Hilal,Andrea Schmidt,Monique Gallandi,Brian Bauer,Thorsten Mielke,Anja Koch,Magdalena Schacherl,Dennis Kwiatkowski,Annette G Beck-Sickinger,Nicolas A Heyder,Gunnar Kleinau Cell Res . 2021 Nov;31(11):1176-1189. doi: 10.1038/s41422-021-00569-8. The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.
4. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials Ulrike Blume-Peytavi,Gregory Gordon,Dirk Schnabel,Ozair Abawi,Jesús Argente,Kathleen De Waele,I Sadaf Farooqi,Guojun Yuan,James M Swain,Goujun Yuan,Gabriel Á Martos-Moreno,Ismaa Sadaf Farooqi,Christa E Flück,Egbert Voss,Murray W Stewart,Peter Kühnen,Natasa Bratina,Christine Poitou,James Swain,Martin Wabitsch,Christian Denzer,Patricia Pigeon-Kherchiche,Katja Kohlsdorf,Wendy K Chung,Lia Puder,Erica van den Akker,Gregory A Gordon,Julia von Schnurbein,Esther Schulz,Anna Flaus-Furmaniuk,Katja Weiss,Julie Gonneau-Lejeune,Susanna Wiegand,Paul Gougis,Allison L Bahm,Philipp Krabusch,Erica L T van den Akker,Hillori Connors,Béatrice Dubern,Setmelanotide POMC and LEPR Phase 3 Trial Investigators,Karine Clément,Hillori S Connors,Knut Mai,Allison Bahm,Alban Danset,Murray Stewart,Martin Bald Lancet Diabetes Endocrinol . 2020 Dec;8(12):960-970. doi: 10.1016/S2213-8587(20)30364-8. Background:The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity.Methods:These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing<100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the propo
