Afamelanotide

Identification

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Name
Afamelanotide
Accession Number
DB04931
Type
Small Molecule
Groups
Approved, Investigational
Description

Afamelanotide is a first-in-class, synthetic, 13-amino acid peptide analogue of the endogenous alpha melanocyte-stimulating hormone (α-MSH).4 It differs structurally from its endogenous counterpart by only two amino acids - these structural differences improve biological efficacy by imparting a greater affinity for its target and a longer biological half-life.2,3 Afamelanotide is currently the only approved drug therapy used in the management of erythropoietic protoporphyria, having received approval in the EU in December 20147 and subsequent FDA approval in October 2019.5 Despite its relatively recent approval, afamelanotide has been available for use as an orphan drug in both the US and EU since 2008.8,9

Structure
Thumb
Synonyms
  • Afamelanotide
  • Melanotan 1
  • Melanotan I
  • Melanotan-1
  • MT-I
External IDs
CUV 1647 / CUV1647 / MBJ 05 / MBJ05
Categories
UNII
QW68W3J66U
CAS number
75921-69-6
Weight
Average: 1646.8452
Monoisotopic: 1645.836510475
Chemical Formula
C78H111N21O19
InChI Key
UAHFGYDRQSXQEB-LEBBXHLNSA-N
InChI
InChI=1S/C78H111N21O19/c1-5-6-19-52(91-75(116)61(41-101)97-72(113)57(34-46-24-26-49(103)27-25-46)94-74(115)60(40-100)88-44(4)102)68(109)92-54(28-29-64(105)106)70(111)96-59(36-48-38-83-42-87-48)73(114)93-56(33-45-16-8-7-9-17-45)71(112)90-53(22-14-31-84-78(81)82)69(110)95-58(35-47-37-85-51-20-11-10-18-50(47)51)67(108)86-39-63(104)89-55(21-12-13-30-79)77(118)99-32-15-23-62(99)76(117)98-65(43(2)3)66(80)107/h7-11,16-18,20,24-27,37-38,42-43,52-62,65,85,100-101,103H,5-6,12-15,19,21-23,28-36,39-41,79H2,1-4H3,(H2,80,107)(H,83,87)(H,86,108)(H,88,102)(H,89,104)(H,90,112)(H,91,116)(H,92,109)(H,93,114)(H,94,115)(H,95,110)(H,96,111)(H,97,113)(H,98,117)(H,105,106)(H4,81,82,84)/t52-,53-,54-,55-,56+,57-,58-,59-,60-,61-,62-,65-/m0/s1
IUPAC Name
(4S)-4-{[(1S)-1-{[(1R)-1-{[(1S)-1-{[(1S)-1-[({[(2S)-6-amino-1-[(2S)-2-{[(1S)-1-carbamoyl-2-methylpropyl]carbamoyl}pyrrolidin-1-yl]-1-oxohexan-2-yl]carbamoyl}methyl)carbamoyl]-2-(1H-indol-3-yl)ethyl]carbamoyl}-4-carbamimidamidobutyl]carbamoyl}-2-phenylethyl]carbamoyl}-2-(1H-imidazol-5-yl)ethyl]carbamoyl}-4-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-acetamido-3-hydroxypropanamido]-3-(4-hydroxyphenyl)propanamido]-3-hydroxypropanamido]hexanamido]butanoic acid
SMILES
CCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(N)=O

Pharmacology

Indication

Afamelanotide is indicated for the prevention of phototoxicity in adult patients with erythropoietic protoporphyria (EPP).4

Associated Conditions
Pharmacodynamics

Afamelanotide increases the production of eumelanin, an endogenous photoprotective agent, to attenuate UV-induced skin damage in patients with a condition that predisposes them to phototoxicity.4 It has a relatively long duration of therapeutic effect despite its short half-life due to its ability to increase melanosome density and therefore skin pigmentation.2 As afamelanotide may darken pre-existing skin pigmentary lesions, patients receiving afamelanotide should undergo a full body skin examination every 6 months to monitor for progression or worsening of any skin abnormalities.4 Standard sun safety measures should continue to be employed during afamelanotide therapy.4

Mechanism of action

Patients with erythropoietic porphyria (EPP) have a deficiency of ferrochelatase (FECH), an enzyme involved in the final step of heme biosynthesis. FECH is required to insert iron into protoporphyrin IX (PPIX) to generate heme, and a deficiency in FECH results in accumulation of PPIX (particularly in the liver and superficial skin vasculature). PPIX molecules are photodynamic - exposure to UV radiation causes these molecules to form reactive oxygen species that lead to subsequent tissue damage.1

Afamelanotide mimics endogenous alpha melanocyte-stimulating hormone (α-MSH), a hormone typically released in response to UV-induced skin damage. Both afamelanotide and α-MSH bind to the melanocortin-1 receptor (MC1R) on melanocytes which stimulates the synthesis of eumelanin, a photoprotective compound. Eumelanin is incorporated into small vesicles called melanosomes which are then distributed to surrounding keratinocytes. Melanosomes are concentrated above the nucleus of these keratinocytes, thus protecting them from UV-induced damage.2 While endogenous α-MSH requires UV-induced skin damage in order to be produced, afamelanotide increases eumelanin biosynthesis independent of UV exposure.3

Activation of MC1R signalling by afamelanotide also instigates other protective processes, including an increase in antioxidant activity, DNA repair, and secretion of immunomodulatory proteins such as interleukin-10.2

TargetActionsOrganism
AMelanocyte-stimulating hormone receptor
agonist
Humans
Absorption

Afamelanotide is administered as a subcutaneous implant that slowly elutes active drug. Most of the dose is released within the first 48 hours, with >90% released by day 5. Plasma levels of afamelanotide decrease slowly over the course of several days following administration - by day 10, plasma levels were undetectable in most clinical trial subjects.4 Following administration of a single subcutaneous implant, the median Tmax was 36 hours, the mean Cmax was 3.7 ± 1.3 ng/mL, and the mean AUC0-∞ was 138.9 ± 42.6 hr.ng/mL.10

Volume of distribution

The apparent volume of distribution of afamelanotide following intravenous administration is approximately 0.54 L/kg.2

Protein binding
Not Available
Metabolism

Details regarding the metabolism and metabolites of afamelanotide are sparse. The drug is more resistant to degradation by serum and proteolytic enzymes than its endogenous counterpart, α-MSH, but presumably undergoes a relatively rapid hydrolysis given its short half-life.4,10 It has been suggested that afamelanotide may be degraded in the same manner as α-MSH but at a much slower rate, or may instead be degraded intracellularly via endocytosis or non-specific proteases.2

Route of elimination

Minimal amounts of unchanged afamelanotide are recovered in the urine following administration, suggesting the drug is extensively metabolized and most likely eliminated primarily via fecal or biliary route.2

Half life

The half-life of afamelanotide is approximately 30 minutes.4 The apparent half-life following administration of a slow-release subcutaneous implant is 15 hours.10

Clearance

Data regarding plasma clearance of afamelanotide are limited. Plasma drug levels are typically undetectable at day 10 following subcutaneous administration of the afamelanotide implant.4,3

Toxicity

Data regarding symptoms or treatment of afamelanotide overdose are currently unavailable.4

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

References

Synthesis Reference

Philippe Wolgen, "Alpha-MSH derivatives for the treatment of photodermatoses" E.U. Patent EP2865422A1, issued Oct. 18, 2017.

General References
  1. Balwani M: Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Jan 24. pii: S1096-7192(18)30641-3. doi: 10.1016/j.ymgme.2019.01.020. [PubMed:30704898]
  2. Minder EI, Barman-Aksoezen J, Schneider-Yin X: Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clin Pharmacokinet. 2017 Aug;56(8):815-823. doi: 10.1007/s40262-016-0501-5. [PubMed:28063031]
  3. Kim ES, Garnock-Jones KP: Afamelanotide: A Review in Erythropoietic Protoporphyria. Am J Clin Dermatol. 2016 Apr;17(2):179-85. doi: 10.1007/s40257-016-0184-6. [PubMed:26979527]
  4. EMA Approved Drugs: Afamelanotide [Link]
  5. FDA News Release: Scenesse [Link]
  6. CaymanChem: Afamelanotide MSDS [Link]
  7. EMA Summary for the Public: Afamelanotide [Link]
  8. FDA Orphan Drugs: Afamelanotide [Link]
  9. EMA Orphan Drugs: Afamelanotide [Link]
  10. FDA Approved Drugs: Afamelanotide [Link]
External Links
PubChem Compound
16197727
PubChem Substance
175426907
ChemSpider
17310725
BindingDB
82411
ChEMBL
CHEMBL441738
Wikipedia
Melanotan
ATC Codes
D02BB02 — Afamelanotide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentVitiligo1
2CompletedTreatmentProtoporphyria, Erythropoietic1
2CompletedTreatmentSolar Urticaria1
2CompletedTreatmentVitiligo1
2Unknown StatusPreventionActinic Keratosis (AK) / Organ Transplant Recipients / Squamous Cell Carcinoma (SCC)1
3CompletedNot AvailablePolymorphic Light Eruption (PLE)1
3CompletedPreventionProtoporphyria, Erythropoietic1
3CompletedTreatmentProtoporphyria, Erythropoietic2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.023 mg/mLALOGPS
logP-1.4ALOGPS
logP-8.2ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)3.46ChemAxon
pKa (Strongest Basic)11.58ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count24ChemAxon
Hydrogen Donor Count23ChemAxon
Polar Surface Area642.98 Å2ChemAxon
Rotatable Bond Count50ChemAxon
Refractivity434.35 m3·mol-1ChemAxon
Polarizability171.61 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9487
Blood Brain Barrier-0.9862
Caco-2 permeable-0.8823
P-glycoprotein substrateSubstrate0.8915
P-glycoprotein inhibitor INon-inhibitor0.8279
P-glycoprotein inhibitor IINon-inhibitor0.7233
Renal organic cation transporterNon-inhibitor0.7765
CYP450 2C9 substrateNon-substrate0.783
CYP450 2D6 substrateNon-substrate0.8117
CYP450 3A4 substrateSubstrate0.5913
CYP450 1A2 substrateNon-inhibitor0.8458
CYP450 2C9 inhibitorNon-inhibitor0.8044
CYP450 2D6 inhibitorNon-inhibitor0.8743
CYP450 2C19 inhibitorNon-inhibitor0.7707
CYP450 3A4 inhibitorNon-inhibitor0.5729
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9007
Ames testNon AMES toxic0.7223
CarcinogenicityNon-carcinogens0.787
BiodegradationNot ready biodegradable0.9916
Rat acute toxicity3.0321 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9494
hERG inhibition (predictor II)Non-inhibitor0.5648
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Peptides / Tyrosine and derivatives / Arginine and derivatives / Phenylalanine and derivatives / Histidine and derivatives / Glutamic acid and derivatives / Valine and derivatives / Proline and derivatives / N-acyl-alpha amino acids and derivatives / Tryptamines and derivatives
show 28 more
Substituents
Polypeptide / Alpha peptide / Tyrosine or derivatives / Arginine or derivatives / Phenylalanine or derivatives / Histidine or derivatives / Glutamic acid or derivatives / Valine or derivatives / Proline or derivatives / N-acyl-alpha amino acid or derivatives
show 55 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.
Gene Name
MC1R
Uniprot ID
Q01726
Uniprot Name
Melanocyte-stimulating hormone receptor
Molecular Weight
34705.04 Da
References
  1. Balwani M: Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Jan 24. pii: S1096-7192(18)30641-3. doi: 10.1016/j.ymgme.2019.01.020. [PubMed:30704898]
  2. Minder EI, Barman-Aksoezen J, Schneider-Yin X: Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clin Pharmacokinet. 2017 Aug;56(8):815-823. doi: 10.1007/s40262-016-0501-5. [PubMed:28063031]
  3. Kim ES, Garnock-Jones KP: Afamelanotide: A Review in Erythropoietic Protoporphyria. Am J Clin Dermatol. 2016 Apr;17(2):179-85. doi: 10.1007/s40257-016-0184-6. [PubMed:26979527]
  4. EMA Approved Drugs: Afamelanotide [Link]

Drug created on October 21, 2007 16:23 / Updated on October 17, 2019 21:30