Design, synthesis, and in vitro biological activity of benzimidazole based factor Xa inhibitors

Z Zhao; D O Arnaiz; B Griedel; S Sakata; J L Dallas; M Whitlow; L Trinh; J Post; A Liang; M M Morrissey; K J Shaw

doi:10.1016/s0960-894x(00)00139-6

Design, synthesis, and in vitro biological activity of benzimidazole based factor Xa inhibitors

Bioorg Med Chem Lett. 2000 May 1;10(9):963-6. doi: 10.1016/s0960-894x(00)00139-6.

Authors

Z Zhao¹, D O Arnaiz, B Griedel, S Sakata, J L Dallas, M Whitlow, L Trinh, J Post, A Liang, M M Morrissey, K J Shaw

Affiliation

¹ Discovery Research, Berlex Biosciences, Richmond, CA 94804-0099, USA. Spring_Zhao@berlex.com

PMID: 10853669
DOI: 10.1016/s0960-894x(00)00139-6

Abstract

Inhibitors based on the benzimidazole scaffold showed subnanomolar potency against Factor Xa with 500-1000-fold selectivity against thrombin and 50-100-fold selectivity against trypsin. The 2-substituent on the benzimidazole ring had a strong impact on the FXa inhibitory activity. Crystallography studies suggest that the 2-substituent may have a conformational effect favoring the extended binding conformation.

MeSH terms

Anticoagulants / chemical synthesis*
Anticoagulants / pharmacology*
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Chemical Phenomena
Chemistry, Physical
Crystallography, X-Ray
Factor Xa Inhibitors*
Humans
Models, Molecular
Molecular Conformation
Structure-Activity Relationship
Thrombin / antagonists & inhibitors
Trypsin Inhibitors / chemical synthesis
Trypsin Inhibitors / pharmacology

Substances

Anticoagulants
Benzimidazoles
Factor Xa Inhibitors
Trypsin Inhibitors
Thrombin