ABSTRACT
Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.
Subject(s)
Aza Compounds/pharmacology , Carboxypeptidase B2/antagonists & inhibitors , Cyclic P-Oxides/pharmacology , Fibrinolytic Agents/pharmacology , Phosphinic Acids/pharmacology , Protease Inhibitors/pharmacology , Animals , Aza Compounds/chemical synthesis , Aza Compounds/metabolism , Carboxypeptidase B2/metabolism , Catalytic Domain , Cyclic P-Oxides/chemical synthesis , Cyclic P-Oxides/metabolism , Fibrinolysis/drug effects , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/metabolism , Humans , Male , Molecular Docking Simulation , Molecular Structure , Phosphinic Acids/chemical synthesis , Phosphinic Acids/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protein Binding , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses. Considering that some similitude exists between S 17625 and probenecid, a compound known to protect against the nephrotoxicity and/or slow the clearance of different drugs, we decided to synthesise some new analogues of S 17625 incorporating some of the salient features of probenecid. Replacement of the chlorine in position 6 by a sulfonylamine led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Amongst the compounds evaluated, derivatives 7a and 7s appear to be the most promising and are currently evaluated in therapeutically relevant stroke models.
