Halothiophene benzimidazoles as P1 surrogates of inhibitors of blood coagulation factor Xa

Werner W K R Mederski; Dieter Dorsch; Soheila Anzali; Johannes Gleitz; Bertram Cezanne; Christos Tsaklakidis

doi:10.1016/j.bmcl.2004.04.097

Halothiophene benzimidazoles as P1 surrogates of inhibitors of blood coagulation factor Xa

Bioorg Med Chem Lett. 2004 Jul 16;14(14):3763-9. doi: 10.1016/j.bmcl.2004.04.097.

Authors

Werner W K R Mederski¹, Dieter Dorsch, Soheila Anzali, Johannes Gleitz, Bertram Cezanne, Christos Tsaklakidis

Affiliation

¹ Merck KGaA, Preclinical Pharmaceutical Research, 64271 Darmstadt, Germany. mederski@merck.de

PMID: 15203158
DOI: 10.1016/j.bmcl.2004.04.097

Abstract

Neutral weak halothiophene benzimidazole inhibitors of the serine protease factor Xa were identified via screening of a compound library. The X-ray crystal structure of representative 3a bound to human fXa confirmed the S1 binding mode. Starting from 3a a series of halothiophene benzimidazoles was synthesized and investigated for their factor Xa inhibitory activity. This led to potent and selective achiral inhibitors against fXa such as compounds 9k and 9w.

MeSH terms

Antithrombins / chemical synthesis*
Antithrombins / pharmacology
Benzimidazoles / chemical synthesis*
Benzimidazoles / pharmacology
Binding Sites
Crystallography, X-Ray
Drug Design
Factor Xa / chemistry
Factor Xa Inhibitors*
Humans
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship
Trypsin / chemistry

Substances

Antithrombins
Benzimidazoles
Factor Xa Inhibitors
Serine Proteinase Inhibitors
benzimidazole
Trypsin
Factor Xa