AFAMELANOTIDE

ID: ALA441738

Max Phase: Approved

First Approval: 2014

Molecular Formula: C78H111N21O19

Molecular Weight: 1646.87

Molecule Type: Protein

Associated Items:

Representations

Synonyms (8): (nle4,d-phe7)-.alpha.-msh | Afamelanotide | Melanotan | Melanotan i | Melanotan-1 | Ndp-alpha-msh | CUV-1647 | CUV1647
Synonyms from Alternative Forms(8):

    Trade Names(1): Scenesse

    Canonical SMILES:  CCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(N)=O)C(C)C

    Standard 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

    Standard InChI Key:  UAHFGYDRQSXQEB-LEBBXHLNSA-N

    Associated Targets(Human)

    MC1R Tclin Melanocortin receptor 1 (2696 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    MC3R Tchem Melanocortin receptor 3 (5659 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    MC4R Tclin Melanocortin receptor 4 (10016 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    MC5R Tchem Melanocortin receptor 5 (4283 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    ADA Tclin Adenosine deaminase (129 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    HEK293 (82097 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    Homo sapiens (32628 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID

    Associated Targets(non-human)

    Mc1r Melanocortin receptor 1 (1101 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    Mc3r Melanocortin receptor 3 (22 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    Mc4r Melanocortin receptor 4 (1205 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    Mc5r Melanocortin receptor 5 (870 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    MCR (36 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID
    Mc3r Melanocortin receptor 3 (1119 Activities)
    Activity TypeRelationActivity valueUnitsAction TypeJournalPubMed IddoiAssay Aladdin ID

    Molecule Features

    Natural Product: NoOral: NoChemical Probe: NoParenteral: Yes
    Molecule Type: ProteinTopical: NoFirst In Class: YesBlack Box: No
    Chirality: YesAvailability: YesProdrug: No

    Drug Indications

    MESH IDMESH Heading EFO IDsEFO TermsMax Phase for IndicationReferences

    Mechanisms of Action

    Mechanism of ActionAction Typetarget IDTarget NameTarget TypeTarget OrganismBinding Site NameReferences

    Properties

    Molecular Weight: 1646.87Molecular Weight (Monoisotopic): 1645.8365AlogP: #Rotatable Bonds:
    Polar Surface Area: Molecular Species: HBA: HBD:
    #RO5 Violations: HBA (Lipinski): HBD (Lipinski): #RO5 Violations (Lipinski):
    CX Acidic pKa: CX Basic pKa: CX LogP: CX LogD:
    Aromatic Rings: Heavy Atoms: QED Weighted: Np Likeness Score:

    References

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    26. Proneth B, Pogozheva ID, Portillo FP, Mosberg HI, Haskell-Luevano C..  (2008)  Melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 modified at the para position of the benzyl side chain (DPhe): importance for mouse melanocortin-3 receptor agonist versus antagonist activity.,  51  (18): [PMID:18800761] [10.1021/jm800291b]
    27. Ruwe AR, Koikov L, Abdel-Malek Z, Haskell-Luevano C, Dirain ML, Portillo F, Xiang Z, Wortman M, Knittel JJ..  (2009)  Semi-rigid tripeptide agonists of melanocortin receptors.,  19  (17): [PMID:19635667] [10.1016/j.bmcl.2009.07.025]
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    32. USP Dictionary of USAN and International Names (2010 edition) and USAN registrations 2007-date, 
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    39. Waszkielewicz AM, Gunia-Krzyżak A, Powroźnik B, Słoczyńska K, Pękala E, Walczak M, Bednarski M, Żesławska E, Nitek W, Marona H..  (2016)  Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.,  24  (8): [PMID:26988801] [10.1016/j.bmc.2016.03.006]
    40. Lensing CJ, Freeman KT, Schnell SM, Adank DN, Speth RC, Haskell-Luevano C..  (2016)  An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers.,  59  (7): [PMID:26959173] [10.1021/acs.jmedchem.5b01894]
    41. WHO Anatomical Therapeutic Chemical Classification, 
    42. Gunia-Krzyżak A, Żelaszczyk D, Rapacz A, Żesławska E, Waszkielewicz AM, Pańczyk K, Słoczyńska K, Pękala E, Nitek W, Filipek B, Marona H..  (2017)  Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.,  25  (2): [PMID:27876250] [10.1016/j.bmc.2016.11.014]
    43. Ericson MD, Freeman KT, Schnell SM, Haskell-Luevano C..  (2017)  A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands.,  60  (2): [PMID:28045525] [10.1021/acs.jmedchem.6b01707]
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    45. Ericson MD, Freeman KT, Schnell SM, Fleming KA, Haskell-Luevano C..  (2017)  Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor.,  60  (19): [PMID:28813605] [10.1021/acs.jmedchem.7b00856]
    46. Ericson MD, Singh A, Tala SR, Haslach EM, Dirain MLS, Schaub JW, Flores V, Eick N, Lensing CJ, Freeman KT, Smeester BA, Adank DN, Wilber SL, Speth R, Haskell-Luevano C..  (2018)  Human β-Defensin 1 and β-Defensin 3 (Mouse Ortholog mBD14) Function as Full Endogenous Agonists at Select Melanocortin Receptors.,  61  (8): [PMID:29578343] [10.1021/acs.jmedchem.8b00251]
    47. Doering SR, Freeman KT, Schnell SM, Haslach EM, Dirain M, Debevec G, Geer P, Santos RG, Giulianotti MA, Pinilla C, Appel JR, Speth RC, Houghten RA, Haskell-Luevano C..  (2017)  Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2.,  60  (10): [PMID:28453292] [10.1021/acs.jmedchem.7b00301]
    48. Fleming KA, Freeman KT, Ericson MD, Haskell-Luevano C..  (2018)  Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists.,  61  (17): [PMID:30035543] [10.1021/acs.jmedchem.8b00684]
    49. Unpublished dataset, 
    50. Winget MD, Ericson MD, Freeman KT, Haskell-Luevano C..  (2020)  Single Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and Efficacy.,  11  (3): [PMID:32184956] [10.1021/acsmedchemlett.9b00198]
    51. Koerperich ZM, Ericson MD, Freeman KT, Speth RC, Pogozheva ID, Mosberg HI, Haskell-Luevano C..  (2020)  Incorporation of Agouti-Related Protein (AgRP) Human Single Nucleotide Polymorphisms (SNPs) in the AgRP-Derived Macrocyclic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Decreases Melanocortin-4 Receptor Antagonist Potency and Results in the Discovery of Melanocortin-5 Receptor Antagonists.,  63  (5): [PMID:31845801] [10.1021/acs.jmedchem.9b00860]
    52. Fleming KA, Freeman KT, Powers MD, Santos RG, Debevec G, Giulianotti MA, Houghten RA, Doering SR, Pinilla C, Haskell-Luevano C..  (2019)  Discovery of Polypharmacological Melanocortin-3 and -4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a μM MC4R Partial Agonist.,  62  (5): [PMID:30741545] [10.1021/acs.jmedchem.9b00053]
    53. Unpublished dataset, 
    54. Ericson MD,Shaikh R,Larson CM,Freeman KT,Haskell-Luevano C.  (2021)  Multiresidue Tetrapeptide Substitutions Yield a 140-fold Selective Melanocortin-3 over Melanocortin-4 Receptor Agonist.,  12  (1): [PMID:33488972] [10.1021/acsmedchemlett.0c00561]
    55. Yuan S,Yu B,Liu HM.  (2020)  New drug approvals for 2019: Synthesis and clinical applications.,  205  [PMID:32911308] [10.1016/j.ejmech.2020.112667]
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