Anthranilamide inhibitors of factor Xa

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• Factor Xa (fXa) is a critical enzyme in the coagulation cascade.
• Developing effective anticoagulants is crucial for managing thrombotic disorders.
• Anthranilamide derivatives have shown promise as enzyme inhibitors.

Purpose of the Study:

• To investigate the structure-activity relationship (SAR) of N(2)-aroyl anthranilamide derivatives.
• To identify novel inhibitors targeting the S1' and S4 sites of factor Xa.
• To develop potent fXa inhibitors with potential for anticoagulation.

Main Methods:

• Synthesis of a series of N(2)-aroyl anthranilamide compounds.
• Exploration of B-ring modifications, including o-aminoalkylether and p-amine probes.
• Evaluation of inhibitor potency using biochemical assays.
• Assessment of anticoagulant activity in vitro assays.

Main Results:

• Specific B-ring substitutions, namely o-aminoalkylether and p-amine probes, were synthesized.
• These modifications led to the discovery of picomolar factor Xa inhibitors.
• The identified inhibitors demonstrated significant efficacy in in vitro anticoagulation assays.

Conclusions:

• The B-ring of N(2)-aroyl anthranilamide derivatives is a key determinant for factor Xa inhibition.
• Novel B-ring probes targeting S1' and S4 sites yield highly potent fXa inhibitors.
• These findings support the development of new anticoagulants based on this scaffold.