ID: ALA264190

Max Phase: Preclinical

Molecular Formula: C34H43N11O5

Molecular Weight: 685.79

Molecule Type: Protein

Representations

Canonical SMILES:  CC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O

Standard InChI:  InChI=1S/C34H43N11O5/c1-20(46)42-29(16-23-18-38-19-41-23)33(50)45-28(14-21-8-3-2-4-9-21)32(49)43-26(12-7-13-39-34(36)37)31(48)44-27(30(35)47)15-22-17-40-25-11-6-5-10-24(22)25/h2-6,8-11,17-19,26-29,40H,7,12-16H2,1H3,(H2,35,47)(H,38,41)(H,42,46)(H,43,49)(H,44,48)(H,45,50)(H4,36,37,39)/t26-,27-,28+,29-/m0/s1

Standard InChI Key:  DFCJPPDAOZROBS-FKWFRFQNSA-N

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Protein

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Properties

Molecular Weight: 685.79

Molecular Weight (Monoisotopic): 685.3449

AlogP: -0.37

#Rotatable Bonds: 18

Polar Surface Area: 265.86

Molecular Species: BASE

HBA: 7

HBD: 10

#RO5 Violations: 2

HBA (Lipinski): 16

HBD (Lipinski): 12

#RO5 Violations (Lipinski): 3

CX Acidic pKa: 11.77

CX Basic pKa: 11.54

CX LogP: -2.01

CX LogD: -3.92

Aromatic Rings: 4

Heavy Atoms: 50

QED Weighted: 0.04

Np Likeness Score: -0.09

References

1. Haskell-Luevano C, Shenderovich MD, Sharma SD, Nikiforovich GV, Hadley ME, Hruby VJ..  (1995)  Design, synthesis, biology, and conformations of bicyclic alpha-melanotropin analogues.,  38  (10): [PMID:7752197] [10.1021/jm00010a018]

2. Haskell-Luevano C, Hendrata S, North C, Sawyer TK, Hadley ME, Hruby VJ, Dickinson C, Gantz I..  (1997)  Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R.,  40  (14): [PMID:9216831] [10.1021/jm960840h]

3. Haskell-Luevano C, Holder JR, Monck EK, Bauzo RM..  (2001)  Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors.,  44  (13): [PMID:11405661] [10.1021/jm010061n]

4. Holder JR, Bauzo RM, Xiang Z, Haskell-Luevano C..  (2002)  Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors. 1. Modifications at the His position.,  45  (13): [PMID:12061882] [10.1021/jm0104872]

5. Holder JR, Bauzo RM, Xiang Z, Haskell-Luevano C..  (2002)  Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors: part 2 modifications at the Phe position.,  45  (14): [PMID:12086493] [10.1021/jm010524p]

6. Holder JR, Bauzo RM, Xiang Z, Scott J, Haskell-Luevano C..  (2003)  Design and pharmacology of peptoids and peptide-peptoid hybrids based on the melanocortin agonists core tetrapeptide sequence.,  13  (24): [PMID:14643357] [10.1016/j.bmcl.2003.08.078]

7. Holder JR, Xiang Z, Bauzo RM, Haskell-Luevano C..  (2002)  Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp position.,  45  (26): [PMID:12477357] [10.1021/jm020296e]

8. Todorovic A, Holder JR, Bauzo RM, Scott JW, Kavanagh R, Abdel-Malek Z, Haskell-Luevano C..  (2005)  N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.,  48  (9): [PMID:15857138] [10.1021/jm0490843]

9. 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]

10. Brabez N, Lynch RM, Xu L, Gillies RJ, Chassaing G, Lavielle S, Hruby VJ..  (2011)  Design, synthesis, and biological studies of efficient multivalent melanotropin ligands: tools toward melanoma diagnosis and treatment.,  54  (20): [PMID:21928837] [10.1021/jm2009937]

11. Haslach EM, Huang H, Dirain M, Debevec G, Geer P, Santos RG, Giulianotti MA, Pinilla C, Appel JR, Doering SR, Walters MA, Houghten RA, Haskell-Luevano C..  (2014)  Identification of tetrapeptides from a mixture based positional scanning library that can restore nM full agonist function of the L106P, I69T, I102S, A219V, C271Y, and C271R human melanocortin-4 polymorphic receptors (hMC4Rs).,  57  (11): [PMID:24517312] [10.1021/jm500064t]

12. Doering SR, Todorovic A, Haskell-Luevano C..  (2015)  Melanocortin antagonist tetrapeptides with minimal agonist activity at the mouse melanocortin-3 receptor.,  6  (2): [PMID:25699138] [10.1021/ml500340z]

13. Singh A, Tala SR, Flores V, Freeman K, Haskell-Luevano C..  (2015)  Synthesis and Pharmacology of α/β(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence.,  6  (5): [PMID:26005535] [10.1021/acsmedchemlett.5b00053]

14. 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]

15. 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]

16. Mowlazadeh Haghighi S, Zhou Y, Dai J, Sawyer JR, Hruby VJ, Cai M..  (2018)  Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation.,  151  [PMID:29679901] [10.1016/j.ejmech.2018.04.021]

17. Lensing CJ, Freeman KT, Schnell SM, Speth RC, Zarth AT, Haskell-Luevano C..  (2018)  Developing a Biased Unmatched Bivalent Ligand (BUmBL) Design Strategy to Target the GPCR Homodimer Allosteric Signaling (cAMP over β-Arrestin 2 Recruitment) Within the Melanocortin Receptors.,  62  (1): [PMID:29669202] [10.1021/acs.jmedchem.8b00238]

18. 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]

19. Doering SR, Freeman K, Debevec G, Geer P, Santos RG, Lavoi TM, Giulianotti MA, Pinilla C, Appel JR, Houghten RA, Ericson MD, Haskell-Luevano C..  (2021)  Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.,  64  (9.0): [PMID:33886285] [10.1021/acs.jmedchem.0c02041]

Source

Source(1):

• Scientific Literature