title: S35225 is a direct inhibitor of Plasminogen Activator Inhibitor type-1 activity in the blood.
abstract: The increased risk of thrombotic events associated with disease states such as diabetes and hypertension has been correlated with elevated circulating levels of Plasminogen Activator Inhibitor type-1 (PAI-1). In the present study we evaluate the benzothiophene derivative S35225 in comparison with two recently described inhibitors of PAI-1 activity Tiplaxtinin and WAY140312 on a panel of PAI-1 activity assays in vitro and in vivo. In a direct chromogenic assay, S35225 has an IC50 value of 44+/-0.9 microM similar to that of Tiplaxtinin (34+/-7 microM) and of WAY140312 (39+/-1 microM). In a clot lysis assay however, S35225 has a significantly lower IC50 value than Tiplaxtinin and WAY140312 (0.6+/-0.3 versus 22+/-5 and 16+/-2 microM respectively). Using a tPA capture assay to quantify active PAI-1 in rat or human plasma, neither WAY140312, nor Tiplaxtinin attained 50% inhibition of PAI-1 activity at the highest concentration tested (1 mM); S35225 has an IC50 value of 194+/-30 microM against active rat PAI-1 and 260+/-41 microM against active human PAI-1. The ability of the compounds to inhibit endogenous active PAI-1 in the rat following intravenous administration was also tested using the tPA capture assay. Only S35225 reduced circulating active PAI-1 levels in vivo (maximum inhibition of 76+/-5% at 10 mg/kg and 53+/-5% at 3 mg/kg). In contrast to Tiplaxtinin and WAY140312, S35225 is a direct inhibitor of PAI-1 activity in vitro in rat and human plasmas where vitronectin is constitutively present as well as in vivo in the blood after an intravenous administration in the rat.
authors.affiliation: Division of Angiology and Medicinal Chemistry, Servier Research Institute, 11 rue des Moulineaux, Suresnes, 92150, France. alain.rupin@fr.netgrs.com
authors.forename: Alain
authors.initials: A
authors.lastname: Rupin
authors.forename: Roger
authors.initials: R
authors.lastname: Gaertner
authors.forename: Philippe
authors.initials: P
authors.lastname: Mennecier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.forename: Alain
authors.initials: A
authors.lastname: Benoist
authors.forename: Guillaume
authors.initials: G
authors.lastname: De Nanteuil
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Verbeuren
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry; D007262:Infusions, Intravenous; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D012306:Risk; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013927:Thrombosis; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000737:chemistry; D019096:Vitronectin / Q000737:chemistry
chemical_list: D001713:Biphenyl Compounds; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; C531328:S 35225; D013876:Thiophenes; D019096:Vitronectin; C488103:tiplaxtinin; D010959:Tissue Plasminogen Activator