Related Experiment Videos
Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1
M L Quan1, A Y Liauw, C D Ellis
1DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
Abstract:
Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.
Insights
Novel biaryl-substituted isoxazoline derivatives effectively inhibit factor Xa (FXa), a key enzyme in blood coagulation. These compounds demonstrate potent antithrombotic efficacy in vivo, offering a promising therapeutic avenue for preventing thrombosis.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Thrombosis is a leading cause of mortality globally.
- Preventing blood coagulation is a critical therapeutic target.
- Inhibiting factor Xa (FXa) is an attractive strategy for antithrombotic therapy.
Purpose of the Study:
- To design and synthesize novel biaryl-substituted isoxazoline derivatives.
- To evaluate the inhibitory potential of these compounds against FXa.
- To assess their in vitro selectivity and in vivo antithrombotic efficacy.
Main Methods:
- Synthesis of novel biaryl-substituted isoxazoline derivatives.
- Biaryl moiety designed for interaction with the FXa S(4) aryl-binding domain.
- In vitro assays for FXa inhibition and selectivity.
- In vivo antithrombotic efficacy testing in a rabbit model.
Main Results:
- Several compounds exhibited low nanomolar affinity for FXa.
- Compounds demonstrated good in vitro selectivity for FXa.
- Potent in vivo antithrombotic efficacy was observed.
- The most potent compounds (33, 35, 37) showed FXa inhibition constants of 3.9, 2.3, and 0.83 nM, respectively.
Conclusions:
- Novel biaryl-substituted isoxazolines are potent inhibitors of FXa.
- These compounds possess favorable in vitro and in vivo antithrombotic properties.
- The developed compounds represent promising candidates for new antithrombotic agents.