Afamelanotide

Identification

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

Afamelanotide is an analog of the peptide hormone alpha-melanocyte stimulating hormone (alpha-MSH) that tends to induce skin tanning. It is being developed by the Australian company Clinuvel Pharmaceuticals (previously known as EpiTan). Afamelanotide was approved in Europe in October, 2014 for the treatment of erythropoietic protoporphyria (EPP). Clinuvel now intends to seek approval of afamelanotide in the United States.

Structure
Thumb
Synonyms
  • Melanotan 1
  • Melanotan I
  • MT-I
External IDs
CUV 1647 / CUV1647 / MBJ 05
International/Other Brands
Scenesse
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

Investigated for use/treatment in actinic keratosis, keratoses, skin cell studies, and skin infections/disorders.

Pharmacodynamics

EPT1647 is a photoprotective agent that acts by increasing the levels of eumelanin in the skin without the need to expose the skin to UV radiation. Therefore, it has the potential to be used as a photoprotective agent for those persons seeking additional protection from UV damage, because their levels of eumelanin do not normally increase when they are exposed to UV radiation or persons who suffer from the clinical symptoms of UV associated skin diseases and disorders, such as Polymorphous Light Eruption (PMLE).

Mechanism of action

EPT1647 stimulates the body to make eumelanin, the dark pigment of the skin which is known to have protective effects on the skin from exposure to both UV-A and UV-B radiation.

TargetActionsOrganism
UMelanocyte-stimulating hormone receptorNot AvailableHumans
Absorption

Absorbed through the skin and distributed throughout the body (systemically).

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

The plasma half-lives following SC dosing (0.08 to 0.21 mg/kg) ranged from 0.07 to 0.79 h for the absorption phase and from 0.8 to 1.7 h for the beta-phase.

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Bhardwaj R, Hadley ME, Dorr RT, Dvorakova K, Brooks C, Blanchard J: Pharmacologic response of a controlled-release PLGA formulation for the alpha-melanocyte stimulating hormone analog, Melanotan-I. Pharm Res. 2000 May;17(5):593-9. [PubMed:10888312]
  2. Ugwu SO, Blanchard J, Dorr RT, Levine N, Brooks C, Hadley ME, Aickin M, Hruby VJ: Skin pigmentation and pharmacokinetics of melanotan-I in humans. Biopharm Drug Dispos. 1997 Apr;18(3):259-69. [PubMed:9113347]
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
3Unknown StatusTreatmentProtoporphyria, Erythropoietic1

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)3.47ChemAxon
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
Polarizability171.62 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
Unknown
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. Fitzgerald LM, Fryer JL, Dwyer T, Humphrey SM: Effect of MELANOTAN, [Nle(4), D-Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles. Peptides. 2006 Feb;27(2):388-94. Epub 2005 Nov 15. [PubMed:16293341]

Drug created on October 21, 2007 16:23 / Updated on November 02, 2018 06:07