title: Halothiophene benzimidazoles as P1 surrogates of inhibitors of blood coagulation factor Xa.
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.
authors.affiliation: Merck KGaA, Preclinical Pharmaceutical Research, 64271 Darmstadt, Germany. mederski@merck.de
authors.forename: Werner W K R
authors.initials: WW
authors.lastname: Mederski
authors.forename: Dieter
authors.initials: D
authors.lastname: Dorsch
authors.forename: Soheila
authors.initials: S
authors.lastname: Anzali
authors.forename: Johannes
authors.initials: J
authors.lastname: Gleitz
authors.forename: Bertram
authors.initials: B
authors.lastname: Cezanne
authors.forename: Christos
authors.initials: C
authors.lastname: Tsaklakidis
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000737:chemistry
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; C031000:benzimidazole; D014357:Trypsin; D015951:Factor Xa