Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Factor Xa (FXa) is a critical enzyme in the coagulation cascade.
• Development of FXa inhibitors is a key strategy for anticoagulant therapy.
• Previous work established potent FXa inhibitors with a pyrazolodihydropyridone core.

Purpose of the Study:

• To explore structure-activity relationships (SAR) of FXa inhibitors.
• To optimize FXa inhibitors by modifying the C-3 substitution and alpha-substitution on the cyclopropyl ring.
• To evaluate the impact of these modifications on FXa binding affinity, anticoagulant activity, and permeability.

Main Methods:

• Systematic modification of the C-3 position of the pyrazolodihydropyridone core.
• Optimization of the alpha-substituent (R group) on the phenylcyclopropyl P4 moiety.
• Assessment of FXa inhibition (FXa K(i)), plasma anticoagulant activity (PT EC(2x)), and cell permeability.
• Evaluation of oral bioavailability in a canine model.
• Testing efficacy in a rabbit arterio-venous shunt thrombosis model.

Main Results:

• Structural modifications significantly influenced FXa binding affinity and anticoagulant properties.
• Optimized compounds demonstrated good oral bioavailability in dogs.
• Selected compounds exhibited high efficacy in a rabbit thrombosis model, with EC(50) values ranging from 29-81 nM.

Conclusions:

• Continuous SAR studies led to the identification of potent and orally bioavailable FXa inhibitors.
• The optimized FXa inhibitors show promise as effective anticoagulants.
• Further development of these compounds could lead to new therapeutic options for thrombotic disorders.