Nonbenzamidine tetrazole derivatives as factor Xa inhibitors

Mimi L Quan; Christopher D Ellis; Ming Y He; Ann Y Liauw; Francis J Woerner; Richard S Alexander; Robert M Knabb; Patrick Y S Lam; Joseph M Luettgen; Pancras C Wong; Matthew R Wright; Ruth R Wexler

doi:10.1016/s0960-894x(02)00951-4

Nonbenzamidine tetrazole derivatives as factor Xa inhibitors

Bioorg Med Chem Lett. 2003 Feb 10;13(3):369-73. doi: 10.1016/s0960-894x(02)00951-4.

Authors

Mimi L Quan¹, Christopher D Ellis, Ming Y He, Ann Y Liauw, Francis J Woerner, Richard S Alexander, Robert M Knabb, Patrick Y S Lam, Joseph M Luettgen, Pancras C Wong, Matthew R Wright, Ruth R Wexler

Affiliation

¹ Bristol-Myers Squibb Co., PO Box 80500, Wilmington, DE 19880-0500, USA. [email protected]

PMID: 12565931
DOI: 10.1016/s0960-894x(02)00951-4

Abstract

Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin.

MeSH terms

Animals
Biological Availability
Dogs
Factor Xa Inhibitors*
Humans
In Vitro Techniques
Kinetics
Models, Molecular
Molecular Mimicry
Protein Conformation
Rabbits
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacokinetics
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship
Tetrazoles / chemical synthesis*
Tetrazoles / pharmacokinetics
Tetrazoles / pharmacology*
Thrombin / antagonists & inhibitors
Trypsin Inhibitors / pharmacology

Substances

Factor Xa Inhibitors
Serine Proteinase Inhibitors
Tetrazoles
Trypsin Inhibitors
Thrombin