Macrocyclic inhibitors for the serine protease plasmin

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Drug Discovery

Background:

• Serine proteases, like plasmin, play critical roles in physiological processes.
• Developing potent and selective inhibitors for proteases is crucial for therapeutic intervention.
• Macrocyclic compounds offer unique structural advantages for drug design.

Purpose of the Study:

• To synthesize and evaluate novel macrocyclic inhibitors targeting the serine protease plasmin.
• To explore the structure-activity relationships of macrocyclic inhibitors based on a cyclohexanone core.
• To assess the potential of these macrocycles to interact with plasmin's binding sites.

Main Methods:

• Synthesis of macrocyclic compounds incorporating a cyclohexanone core and peptide fragments.
• Linking of the cyclohexanone core to either the C- or N-terminus of peptides.
• Formation of macrocycles by connecting amino acid side chains (Tyr or Trp) via linkers.
• In vitro evaluation of inhibitor activity against plasmin.

Main Results:

• Successful synthesis of a series of macrocyclic inhibitors.
• Inhibitors were designed to target both primed and non-primed binding sites of plasmin.
• Macrocyclic inhibitors exhibited up to 10-fold greater potency than their non-cyclic counterparts.
• Observed activities were modest, indicating room for further optimization.

Conclusions:

• Macrocyclization represents a viable strategy to enhance the potency of plasmin inhibitors.
• The developed macrocyclic scaffolds show promise for further development into therapeutic agents.
• Structural modifications can be explored to improve the potency and selectivity of these inhibitors.