Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Drug Discovery

Background:

• Factor VIIa (FVIIa) is a key enzyme in the coagulation cascade.
• Developing selective FVIIa inhibitors is crucial for treating bleeding disorders and thrombosis.
• Previous efforts focused on acyclic inhibitors, with limited success in achieving oral bioavailability.

Purpose of the Study:

• To design and synthesize novel macrocyclic inhibitors targeting FVIIa.
• To optimize inhibitor potency, selectivity, and pharmacokinetic properties.
• To explore the potential of macrocyclic scaffolds for orally bioavailable FVIIa inhibitors.

Main Methods:

• Structure-based drug design utilizing a phenylpyrrolidine lead and molecular modeling.
• Synthesis of a novel series of macrocyclic FVIIa inhibitors.
• Biochemical assays to determine inhibitory potency (Ki) and selectivity against serine proteases.
• Functional assays to assess prothrombin time in FVII-deficient plasma.

Main Results:

• A 16-membered macrocycle demonstrated a 60-fold increase in potency compared to its acyclic counterpart.
• Further optimization yielded a macrocycle with a TF/FVIIa Ki of 1.6 nM.
• The optimized macrocycle exhibited excellent selectivity against seven serine proteases and a functional FVII-deficient prothrombin time EC2x of 1.2 μM.

Conclusions:

• A potent and selective macrocyclic scaffold for FVIIa inhibition was successfully discovered.
• This macrocyclic scaffold holds significant promise for the development of orally bioavailable FVIIa inhibitors.
• The findings open new avenues for therapeutic strategies targeting coagulation disorders.