RESUMEN
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.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinas/química , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Diseño de Fármacos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzazepinas/síntesis química , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/química , Tetrahidroisoquinolinas/química , Administración Oral , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Estructura Molecular , Ratas , Inhibidores de Serina Proteinasa/administración & dosificación , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/farmacologíaRESUMEN
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.
Asunto(s)
Anticoagulantes/química , Factor X/antagonistas & inhibidores , Pirrolidinonas/química , Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Factor X/metabolismo , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inhibidores del Factor Xa , Pirrolidinonas/química , Inhibidores de Serina Proteinasa/química , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Oxitocina/antagonistas & inhibidores , Piperazinas/química , Piperazinas/farmacología , Animales , Femenino , Humanos , Cinética , Oxitocina/metabolismo , Piperazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Oxitocina/metabolismo , Relación Estructura-Actividad , Contracción Uterina/efectos de los fármacosRESUMEN
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.
Asunto(s)
Indenos/síntesis química , Piperazinas/síntesis química , Receptores de Oxitocina/antagonistas & inhibidores , Administración Oral , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Unión Competitiva , Disponibilidad Biológica , Células CHO , Señalización del Calcio/efectos de los fármacos , Cricetinae , Cricetulus , Perros , Humanos , Indenos/farmacocinética , Indenos/farmacología , Oxitocina/farmacología , Piperazinas/farmacocinética , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Contracción Uterina/efectos de los fármacosRESUMEN
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.