ABSTRACT
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Anticoagulants/chemical synthesis , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Antithrombin III/pharmacokinetics , Crystallography, X-Ray , Dogs , Humans , Male , Pyridones/pharmacokinetics , Pyrrolidines/pharmacokinetics , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
Subject(s)
Antithrombin III/chemistry , Chemistry, Pharmaceutical/methods , Pyrrolidonecarboxylic Acid/pharmacology , Administration, Oral , Animals , Antithrombin III/pharmacology , Crystallization , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Protein Binding , Pyrrolidonecarboxylic Acid/chemistry , Structure-Activity Relationship , Time FactorsABSTRACT
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
