Design, synthesis, and biological activity of potent and selective inhibitors of blood coagulation factor Xa

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Factor Xa (FXa) is a critical enzyme in the blood coagulation cascade.
• FXa's role in thrombin generation makes it a significant target for antithrombotic drug development.

Purpose of the Study:

• To design and synthesize novel quinoxalinone-based inhibitors of FXa.
• To evaluate the potency, selectivity, and in vivo efficacy of a lead compound.

Main Methods:

• Chemical synthesis of quinoxalinone derivatives.
• Enzyme inhibition assays to determine potency and selectivity.
• X-ray crystallography and molecular modeling for structural insights.
• In vivo efficacy studies in rabbit and dog models.
• Pharmacokinetic and bleeding time assessments.

Main Results:

• A novel series of quinoxalinone FXa inhibitors was synthesized.
• Compound 35 exhibited potent FXa inhibition (0.83 nM) and high selectivity.
• Structural analysis predicted compound 35's binding conformation in FXa.
• Compound 35 demonstrated in vivo efficacy in thrombosis models.
• Compound 35 showed a dose-dependent increase in plasma concentration and minimal impact on bleeding times at therapeutic doses.

Conclusions:

• The synthesized quinoxalinone derivatives represent a promising class of FXa inhibitors.
• Compound 35 is a potent and selective FXa inhibitor with demonstrated in vivo efficacy and a potentially manageable safety profile for antithrombotic therapy.