Atropisomer Control in Macrocyclic Factor VIIa Inhibitors

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Macrocyclic inhibitors targeting Factor VIIa (FVIIa) are crucial in anticoagulant therapy.
• Incorporating a methyl group enhanced inhibitor potency but introduced atropisomerism, complicating development.

Purpose of the Study:

• To design and synthesize a conformationally constrained macrocyclic FVIIa inhibitor.
• To favor the desired atropisomer and improve inhibitor potency and selectivity.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy to assess conformation and atropisomerism.
• Rational drug design incorporating conformational constraints.
• X-ray crystallography to determine the inhibitor's binding mode.

Main Results:

• A conformational constraint was successfully introduced, favoring the desired atropisomer.
• The constrained inhibitor exhibited an 180-fold increase in potency and improved selectivity.
• X-ray crystallography confirmed the designed interaction of the methyl group with the FVIIa S2 pocket.

Conclusions:

• Conformationally stable macrocyclic FVIIa inhibitors can be rationally designed.
• This approach provides a robust template for further optimization of FVIIa inhibitors.