Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Hematology

Background:

• A significant need exists for safe oral therapies to manage thrombotic disorders.
• The serine protease factor Xa (fXa) is a key target for developing novel anticoagulant drugs.
• Previous drug discovery efforts have focused on fXa inhibition for antithrombotic treatments.

Purpose of the Study:

• To discover and optimize novel oral inhibitors of factor Xa (fXa).
• To identify compounds with high potency, selectivity, and favorable pharmacokinetic profiles for anticoagulant therapy.

Main Methods:

• High-throughput screening identified initial thiophene-substituted anthranilamide hits.
• Lead optimization involved incorporating hydrophilic groups to enhance inhibitory potency and activity.
• In vitro assays assessed inhibitory potency and anticoagulant activity.
• In vivo studies evaluated oral pharmacokinetics and efficacy in a rat thrombosis model.

Main Results:

• A series of potent nonamidine fXa inhibitors were discovered.
• Optimized compounds exhibited picomolar inhibitory potency and micromolar in vitro anticoagulant activity.
• Compounds demonstrated favorable oral pharmacokinetics and efficacy in a rat venous stasis thrombosis model.
• Compounds ZK 814048, ZK 810388, and ZK 813039 were selected for further development.

Conclusions:

• Thiophene-substituted anthranilamides represent a promising class of oral factor Xa inhibitors.
• The identified compounds show potential as safe and effective therapies for thrombotic disorders.
• Further development of these compounds may address the unmet medical need for oral anticoagulants.