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. 2018 May 10;61(9):4263-4269.
doi: 10.1021/acs.jmedchem.8b00488. Epub 2018 Apr 25.

Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

Francesco Merlino  1 , Yang Zhou  2 , Minying Cai  2 , Alfonso Carotenuto  1 , Ali M Yousif  1 , Diego Brancaccio  1 , Salvatore Di Maro  3 , Silvia Zappavigna  4 , Antonio Limatola  5 , Ettore Novellino  1 , Paolo Grieco  1 , Victor J Hruby  2
Affiliations

Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

Francesco Merlino et al. J Med Chem. .

Abstract

We report the development of macrocyclic melanocortin derivatives of MT-II and SHU-9119, achieved by modifying the cycle dimension and incorporating constrained amino acids in ring-closing. This study culminated in the discovery of novel agonists/antagonists with an unprecedented activity profile by adding pieces to the puzzle of the melanocortin receptor selectivity. Finally, the resulting 19- and 20-membered rings represent a suitable frame for the design of further therapeutic ligands as selective modulators of the melanocortin system.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Lowest energy conformers of compound 8 (PDB code 6FCE).
Figure 2
Figure 2
(a) hMC3R model complexed with 8. Heavy atoms of 8 (carbon, green; nitrogen, blue; oxygen, red; sulfur, yellow). Receptor backbone is represented in gray ribbon. (b) 8 within the binding pocket of hMC3R. Hydrogen bonds are represented with dashed lines.
Chart 1
Chart 1
Chemical Structures and Ring Cycle Dimension of MT-II (1), SHU-9119 (2), and PG10N (3)
Chart 2
Chart 2
Chemical Structures and Ring Cycle Dimension of Synthesized Compounds 4–19 Divided as Series A and B (19- and 20-Membered Rings, Respectively)
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