Repositioning Candidate Details
| Candidate ID: | R1393 |
| Source ID: | DB11700 |
| Source Type: | approved; investigational |
| Compound Type: | small molecule |
| Compound Name: | Setmelanotide |
| Synonyms: | Setmelanotide |
| Molecular Formula: | C49H68N18O9S2 |
| SMILES: | [H]N([H])C(=O)[C@@H]1CSSC[C@H](N([H])C(=O)[C@H](CCCN=C(N([H])[H])N([H])[H])N([H])C(C)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC2=CN=CN2[H])C(=O)N[C@H](CC2=CC=CC=C2)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC2=CN([H])C3=CC=CC=C23)C(=O)N1 |
| Structure: |
|
| DrugBank Description: | 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. |
| CAS Number: | 920014-72-8 |
| Molecular Weight: | 1117.32 |
| DrugBank Indication: | Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin deficiency, proprotein subtilisin/kexin type 1 deficiency, or leptin receptor deficiency. These conditions affect the MC4R signalling pathway. |
| DrugBank Pharmacology: | 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. |
| DrugBank MoA: | 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 EC<sub>50</sub> 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. |
| Targets: | Melanocortin receptor 4 agonist |
| Inclusion Criteria: | Therapeutic strategy associated |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I17 | 1596 | Mental depression | Mental depression | disease of mental health/ cognitive disorder/ mood disorder | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| I15 | 1290 | Bone disease | A connective tissue disease that affects the structure or development of bone or causes an impairment of normal bone function. http://en.wikipedia.org/wiki/Bone_disease | disease of anatomical entity/ musculoskeletal system disease/connective tissue disease | Details |