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
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.
Subject(s)
Oxytocin/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Animals , Female , Humans , Kinetics , Oxytocin/metabolism , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Oxytocin/metabolism , Structure-Activity Relationship , Uterine Contraction/drug effectsABSTRACT
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
A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.
Subject(s)
Indenes/chemical synthesis , Piperazines/chemical synthesis , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Antidiuretic Hormone Receptor Antagonists , Binding, Competitive , Biological Availability , CHO Cells , Calcium Signaling/drug effects , Cricetinae , Cricetulus , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Oxytocin/pharmacology , Piperazines/pharmacokinetics , Piperazines/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship , Uterine Contraction/drug effectsABSTRACT
This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds.