ABSTRACT
The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.
Subject(s)
Factor Xa Inhibitors , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Drug Design , Models, Molecular , Structure-Activity RelationshipABSTRACT
The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.
Subject(s)
Benzazepines/chemical synthesis , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemistry , Tetrahydroisoquinolines/chemistry , Administration, Oral , Animals , Benzazepines/administration & dosage , Benzazepines/pharmacology , Crystallography, X-Ray , Drug Evaluation, Preclinical , Molecular Structure , Rats , Serine Proteinase Inhibitors/administration & dosage , Tetrahydroisoquinolines/administration & dosage , Tetrahydroisoquinolines/pharmacologyABSTRACT
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.
Subject(s)
Anticoagulants/chemistry , Factor X/antagonists & inhibitors , Pyrrolidinones/chemistry , Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Design , Factor X/metabolism , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacology , Structure-Activity RelationshipABSTRACT
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Factor Xa Inhibitors , Pyrrolidinones/chemistry , Serine Proteinase Inhibitors/chemistry , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Hydrophobic and Hydrophilic Interactions , Male , Models, Molecular , Pyrrolidinones/pharmacokinetics , Pyrrolidinones/pharmacology , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
