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Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)
Donald J P Pinto1, Michael J Orwat1, Leon M Smith1
1Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
Abstract:
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.
Insights
Researchers discovered BMS-962212, a potent small molecule inhibitor of Factor XIa (FXIa). This drug candidate shows promise for acute antithrombotic therapy in hospitals, effectively blocking clot formation without impairing normal hemostasis.
Area of Science:
- Biochemistry
- Pharmacology
- Hematology
Background:
- Factor XIa (FXIa) is a key enzyme in blood coagulation, amplifying thrombin generation.
- Inhibiting FXIa is a promising strategy for antithrombotic therapy, potentially preventing pathological thrombosis while maintaining hemostasis.
- Developing FXIa inhibitors for acute hospital-based treatments is an active area of research.
Purpose of the Study:
- To discover and characterize potent, selective small molecule inhibitors of FXIa.
- To identify a clinical candidate suitable for intravenous administration as an acute antithrombotic agent.
- To evaluate the preclinical efficacy and safety profile of novel FXIa inhibitors.
Main Methods:
- Screening for and optimizing small molecule inhibitors targeting FXIa.
- Biochemical assays to determine inhibitor potency (e.g., Ki values) and selectivity.
- Preclinical thrombosis models to assess antithrombotic efficacy and bleeding risk.
Main Results:
- Discovery of compound 55 (BMS-962212), a potent FXIa inhibitor with a Ki of 0.7 nM.
- Demonstrated excellent preclinical antithrombotic efficacy in relevant thrombosis models.
- Compound 55 exhibits suitable aqueous solubility for intravenous administration and is a reversible, direct, and highly selective inhibitor.
Conclusions:
- BMS-962212 is a promising clinical candidate for FXIa inhibition.
- This compound has potential as an acute antithrombotic agent for hospital settings.
- The findings support the therapeutic potential of direct FXIa inhibition in managing thrombotic events.
