S35225 is a direct inhibitor of Plasminogen Activator Inhibitor type-1 activity in the blood.
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.
Rupin
Alain
A
Division of Angiology and Medicinal Chemistry, Servier Research Institute, 11 rue des Moulineaux, Suresnes, 92150, France. alain.rupin@fr.netgrs.com
Gaertner
Roger
R
Mennecier
Philippe
P
Richard
Isabelle
I
Benoist
Alain
A
De Nanteuil
Guillaume
G
Verbeuren
Tony J
TJ
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
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