setmelanotide   Click here for help

GtoPdb Ligand ID: 9272

Synonyms: BIM-22493 | IRC-022493 | RM-493
Comment: Setmelanotide is an investigational agonist of melanocortin receptors, with approximately 20-fold selectivity for the melanocortin 4 receptor subtype [4]. Chemically it is an eight-amino-acid cyclic peptide, able to cross the blood-brain barrier when administered peripherally. Setmelanotide is being investigated for its anti-obesity potential.

HELM annotation : PEPTIDE1{[ac].R.C.[dA].H.[dF].R.W.C.[am]}$PEPTIDE1,PEPTIDE1,3:R3-9:R3$$$
INN record documents the sequence as N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide.
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2D Structure
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SMILES / InChI / InChIKey
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Canonical SMILES NC(=NCCCC(C(=O)NC1CSSCC(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC1=O)C)Cc1[nH]cnc1)Cc1ccccc1)CCCN=C(N)N)Cc1c[nH]c2c1cccc2)C(=O)N)NC(=O)C)N
Isomeric SMILES NC(=NCCC[C@@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)[C@H](NC1=O)C)Cc1[nH]cnc1)Cc1ccccc1)CCCN=C(N)N)Cc1c[nH]c2c1cccc2)C(=O)N)NC(=O)C)N
InChI InChI=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
InChI Key HDHDTKMUACZDAA-PHNIDTBTSA-N
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Summary of Clinical Use Click here for help
Phase 1 results from NCT01867437 indicated that short-term administration of setmelanotide (RM-493) increased resting energy expenditure and shifted substrate oxidation to fat [1]. A Phase 2 trial in an extremely restircted patient population with the ultra-rare disease, proopiomelanocortin deficiency (NCT02507492), reported a reduction in hyperphagia and substantial and sustained weight loss [5]. Phase 2 and 3 trials in patients with other genetic forms of obesity (e.g. leptin receptor deficiency, Prader-Willi syndrome, Bardet Biedl syndrome and Alström syndrome) are ongoing as of Jan 2019. Click here to link to ClinicalTrials.gov's full list of setmelanotide trials.
Setmelanotide has not yet been found to cause hypertension, a common adverse effect reported with other melanocortin agonist drugs. One side-effect of setmelanotide treatment is darkening of the skin and hair, likely as a result of off-target activation of melanocortin receptors (MC1R) in peripheral melanoctyes.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Melanocortin-4 receptor (MC4R) has a central role in the brain's regulation of appetite and energy control. That mutations in the gene encoding melanocortin receptor agonists, or the MC4R gene have been reported to cause obesity [3], confirms MC4R activation as a pharmacological intervention with potential benefit in obesity treatment [2]. Although not a deficiency of MC4R, proopiomelanocortin deficiency patients lack the hormones derived from proopiomelanocortin (adrenocorticotropic hormone (ACTH) and the melanocyte-stimulating hormones). So, in these patients setmelanotide is being used as hormone replacement therapy, to reinstate MC4R activity in the brain and regain control of appetite and energy expenditure.