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1.
Bioorg Med Chem ; 17(6): 2501-11, 2009 Mar 15.
Article in English | MEDLINE | ID: mdl-19231206

ABSTRACT

Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).


Subject(s)
Pyrrolidines/pharmacology , Administration, Oral , Crystallography, X-Ray , Half-Life , Humans , Pyrrolidines/administration & dosage , Pyrrolidines/pharmacokinetics
2.
Chem Biol Drug Des ; 70(2): 100-12, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17683371

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 Relationship
3.
Chem Biol Drug Des ; 69(6): 444-50, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17581239

ABSTRACT

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 Factors
4.
J Med Chem ; 47(16): 4089-99, 2004 Jul 29.
Article in English | MEDLINE | ID: mdl-15267248

ABSTRACT

Factor Xa (FXa) has materialized as a key enzyme for the intervention of the blood coagulation cascade and for the development of new antithrombotic agents. FXa is the lone enzyme responsible for the production of thrombin and therefore is an attractive target for the control of thrombus formation. We have designed and synthesized a unique series of quinoxalinone FXa inhibitors. This series resulted in 3-[4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3-oxo-3,4-dihydroquinoxolin-2-yl]benzamidine (35) with 0.83 nM activity against FXa and excellent selectivity over similar serine proteases. An X-ray crystal structure of compound 35 bound to trypsin along with molecular modeling has led to a predicted binding conformation of compound 35 in FXa. Compound 35 has also been proven to be efficacious in vivo in both the rabbit veno-venous shunt and dog electrolytic injury models. In addition, it was shown that compound 35 did not significantly increase bleeding times in a rabbit model except at the highest doses and plasma concentrations were elevated in a dose dependent manner following a bolus dose and continuous intravenous infusion.


Subject(s)
Anticoagulants/chemical synthesis , Benzamidines/chemical synthesis , Factor Xa Inhibitors , Quinoxalines/chemical synthesis , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacology , Benzamidines/chemistry , Benzamidines/pharmacology , Crystallography, X-Ray , Dogs , Drug Design , Factor Xa/chemistry , Humans , In Vitro Techniques , Molecular Structure , Protein Binding , Quinoxalines/chemistry , Quinoxalines/pharmacology , Rabbits , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Species Specificity , Thrombosis/pathology , Thrombosis/prevention & control
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