Side-chain-constrained amino acids
are useful tools to modulate
the biological properties of peptides. In this study, we applied side-chain
constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13
positions, affecting the binding affinity and signaling profile on
the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found
to be beneficial substitutions for Pro12, and the resulting analogues
displayed high affinity for APJ (K
i
0.08–0.18 nM vs Ape13 K
i
0.7 nM). Besides, constrained (d-Tic) or
α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, K
i
0.08 nM) and 53 (Pro12-Phe13
replaced by 1Nal–Dbzg, K
i
0.08 nM) are the most potent Ape13 analogues activating
the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known
to date, displaying high affinity, resistance to ACE2 cleavage as
well as improved pharmacokinetics in vitro (t
1/2 5.8–7.3 h in rat plasma) and in vivo.
Herein, the synthesis of novel conformationally constrained amino acids, 4-amino-8-bromo-2-benzazepin-3-one (8-Br-Aba), 3-amino-3,4-dihydroquinolin-2-one, and regioisomeric 4-amino-naphthoazepinones (1- and 2-Ana), is described. Introduction of these constricted scaffolds into the -terminal tetrapeptide of dermorphin (i.e., H-Tyr-d-Ala-Phe-Gly-NH) induced significant shifts in binding affinity, selectivity, and in vitro activity at the μ- and δ-opioid receptors (MOP and DOP, respectively). A reported constrained μ-/δ-opioid lead tetrapeptide H-Dmt-d-Arg-Aba-Gly-NH was modified through application of various constrained building blocks to identify optimal spatial orientations in view of activity at the opioid receptors. Interestingly, when the aromatic moieties were turned toward the -terminus of the peptide sequences, (partial) (ant)agonism at MOP and weak (ant)agonism at DOP were noticed, whereas the incorporation of the 1-Ana residue led toward balanced low nanomolar MOP/DOP binding and in vitro agonism.
A 3-step methodology for the synthesis of 1,5-benzothiazepin-4(5H)-one dipeptidomimetics has been elaborated via an Ugi-4CR followed by a S-trityl deprotection and an intramolecular Cu(i)-catalyzed Ullmann condensation with moderate to good yields. In silico and NMR conformational studies showed that the lowest energy conformers stabilize γ- and β-turn structures.
Apelin
is an endogenous peptide that is involved in many diseases
such as cardiovascular diseases, obesity, and cancer, which has made
it an attractive target for drug discovery. Herein, we explore the
penultimate and final sequence positions of [Pyr1]-apelin-13
(Ape13) via C-terminal N
α-alkylated
amide bonds and the introduction of positive charges, potentially
targeting the allosteric sodium pocket, by assessing the binding affinity
and signaling profiles at the apelin receptor (APJ). Synthetic analogues
modified within this segment of Ape13 showed high affinity (K
i 0.12–0.17 nM vs Ape13 K
i 0.7 nM), potent Gαi1 activation (EC50 Gαi1 0.4–0.9 nM vs Ape13 EC50 1.1 nM), partial agonist behavior disfavoring β-arrestin
2 recruitment for positively charged ligands (e.g., 49 (SBL-AP-058), EC50 β-arr2 275 nM, E
max 54%) and high plasma stability for N-alkyl ligands (t
1/2 > 7
h
vs Ape13 t
1/2 0.5 h). Combining the benefits
of the N
α-alkylated amide bond with
the guanidino substitution in a constrained ligand led to 63 (SBL-AP-049), which displayed increased plasma stability
(t
1/2 5.3 h) and strong reduction of β-arrestin
2 signaling with partial maximal efficacy (EC50 β-arr
864 nM, E
max 48%), significantly reducing
the hypotensive effect in vivo.
An efficient three step synthesis towards 3-amino-1,4-benzodiazepin-2-one derivatives is presented. The versatile Ugi-4-component reaction (Ugi-4CR) and Boc-deprotection is followed by a ligand-free Ullmann condensation. This protocol allows the rapid construction of a diverse array of substituted 1,5-benzodiazepinones. Since Ugi-based products are typically limited by their ‘inert’ C-terminal amides, the use of a convertible (‘cleavable’) isocyanide was envisaged and resulted in building blocks that can be made SPPS-compatible. To demonstrate the potential of this novel synthetic route, the design and preparation of novel phenylurea-1,5-bezondiazepin-4(5H)-one dipeptide mimetics with potential CCK2-antagonist properties is reported.
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