Setmelanotide API Manufacturers

General Description:

Setmelanotide, identified by CAS number 920014-72-8, is a notable compound with significant therapeutic applications. Setmelanotide is the first available treatment for patients with pro-opiomelanocortin, proprotein subilisin/kexin type 1, or leptin deficiencies. It is an agonist of the melanocortin 4 receptor. Earlier attempts at agonizing MC4R (such as LY2112688) lead to successful weight loss, but also an increase in blood pressure and heart rate. Other earlier treatments for these patients included gastric bypass surgery. Patients taking setmelanotide experienced an average weight loss of 0.6 kg/week. Imcivree was granted EMA orphan designation on 19 November 2018 and FDA approval on 25 November 2020.

Indications:

This drug is primarily indicated for: Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance. These conditions affect the MC4R signalling pathway. Setmelanotide is also indicated for chronic weight management in patients 6 years and older with obesity due to Bardet-Biedl syndrome. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Setmelanotide undergoes metabolic processing primarily in: Setmelanotide is expected to be metabolized to small peptides and amino acids. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Setmelanotide are crucial for its therapeutic efficacy: Setmelanotide has a T_max of 8 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Setmelanotide is an important consideration for its dosing schedule: The elimination had life of setmelanotide is approximately 11 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Setmelanotide exhibits a strong affinity for binding with plasma proteins: Setmelanotide is 79.1% protein bound. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Setmelanotide from the body primarily occurs through: A 3mg subcutaneous dose of setmelanotide is 39% eliminated in the urine as the unchanged parent compound. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Setmelanotide is distributed throughout the body with a volume of distribution of: The apparent volume of distribution of setmelanotide is 48.7 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Setmelanotide is a critical factor in determining its safe and effective dosage: A 3mg subcutaneous dose of setmelanotide has an estimated clearance of 4.86 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Setmelanotide exerts its therapeutic effects through: Setmelanotide agonizes MC4R, downstream of multiple potential genetic deficiencies, to induce a feeling of satiety for chronic weight management. It has a moderate duration of action as it is given daily. Patients should be counselled regarding the risk of disturbances in sexual arousal, depression and suicidal ideation, and darkening of skin pigmentation. Exercise caution in neonates and low birth weight infants, as they may experience serious adverse effects due to benzyl alcohol. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Setmelanotide functions by: Grehlin and other hunger signals from the gastrointestinal tract stimulate orexigenic neurons, stimulating the release of agouti-related protein. Agouti-related protein inhibits melanocortin 4 receptor (MC4R) activation until satiety signals such as insulin or leptin stimulate anorexigenic neurons. Insulin and leptin stimulate production of the POMC-derived melanocortin peptide α-melanocyte simulating hormone, which is a ligand of MC4R. Orexigenic and anorexigenic neurons contain prohormone convertase 1/3 (PC1/3), which is encoded by the gene proprotein subtilisin/kexin type 1. PC1/3 preforms activation cleavage of a number of peptide hormone precursors, including α-melanocyte simulating hormone. Setmelanotide is a pro-opiomelanocortin derived peptide that is an agonist of MC4R. It is an approximately 20-fold more potent agonist of MC4R than endogenous α-melanocyte stimulating hormone, with an EC₅₀ of 0.27 nM. By directly agonizing MC4R, upstream genetic deficiencies in the MC4R signalling pathway cannot inhibit satiety, food intake is decreased, and weight loss is achieved. MC4R is a 332 amino acid G-protein coupled receptor (G-PCR). Although the lack of cardiovascular adverse effects with setmelanotide treatment are not well understood, it is believed that earlier MC4R antagonists activated multiple G-protein signalling pathways. Earlier drugs that targeted G-PCRs either bound with high affinity to the highly conserved orthosteric binding site, or with high specificity to less conserved allosteric sites. Setmelanotide is an atypical bitopic ligand that interacts with both the orthosteric and putative allosteric binding site, allowing for both high affinity and specificity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Setmelanotide belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds, classified under the direct parent group Oligopeptides. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Categories:

Setmelanotide is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Amino Acids, Peptides, and Proteins, Anti-Obesity Agents, Antiobesity Preparations, Excl. Diet Products, Centrally Acting Antiobesity Products, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Hypothalamic Hormones, Melanocortin 4 Receptor Agonist, Melanocortin 4 Receptor Agonists, Melanocortins, Melanocyte-Stimulating Hormones, Nerve Tissue Proteins, Neuropeptides, Peptide Hormones, Peptides, Pituitary Hormones, Pituitary Hormones, Anterior, Pro-Opiomelanocortin, Protein Precursors, Proteins, Receptor, Melanocortin, Type 4, agonists. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.