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
BACKGROUND: Factor Xa (FXa) has been a target of considerable interest for drug development efforts aimed at suppressing thrombosis. In this report, a new orally active, small molecule, active-site directed FXa inhibitor, GW813893, has been profiled in a succession of in vitro and in vivo assays involved in its preclinical characterization as a potential antithrombotic therapeutic. METHODS: In vitro profiling of GW813893 consisted of assessing its inhibitory potential against FXa and a broad panel of related and unrelated enzymes and receptors. Additionally, the FXa inhibition potential of GW813893 was assessed in prothrombinase and plasma-based clotting assays. In vivo characterization of GW813893 consisted of thrombosis studies in a rat inferior vena cava model, a rat carotid artery thrombosis model, and a rabbit jugular thrombosis model. Bleeding studies were conducted in a rat tail transection model. Ex vivo determinations of compound effects on FX and clotting activity were also undertaken. RESULTS: GW813893 was more than 90-fold selective over all enzymes tested, and it inhibited FXa and prothrombinase activity with a Ki of 4.0 nM and 9.7 nM, respectively. In vivo, GW813893 concentration-dependently suppressed thrombotic activity in all models tested. The antithrombotic activity correlated with the suppression of plasma-based clotting activity and the inhibition of plasma FX activity (P < 0.02). Over the antithrombotic dose-range, an increased bleeding diathesis was not observed. CONCLUSION: These experiments demonstrate that GW813893 is a potent, selective, orally active inhibitor of FXa. The data suggest that GW813893 has robust antithrombotic potential at doses that have no detectable hemostasis liability. Collectively, the profile suggests that GW813893 has the preclinical pharmacology underpinnings of an oral antithrombotic therapeutic.
Asunto(s)
Inhibidores del Factor Xa , Fibrinolíticos/farmacología , Pirrolidinonas/farmacología , Sulfonamidas/farmacología , Administración Oral , Animales , Tiempo de Sangría , Pruebas de Coagulación Sanguínea , Trombosis de las Arterias Carótidas/tratamiento farmacológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fibrinolíticos/uso terapéutico , Venas Yugulares , Masculino , Pirrolidinonas/uso terapéutico , Conejos , Ratas , Ratas Sprague-Dawley , Sulfonamidas/uso terapéutico , Vena Cava Inferior , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
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
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.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinonas/química , Pirrolidinonas/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Diseño de Fármacos , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Asunto(s)
Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Factor Xa/química , Morfolinas/síntesis química , Pirrolidinas/síntesis química , Sulfonamidas/síntesis química , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Cristalografía por Rayos X , Perros , Femenino , Humanos , Ligandos , Masculino , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Morfolinas/farmacología , Unión Proteica , Tiempo de Protrombina , Pirrolidinas/química , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/química , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Inhibitors of transforming growth factor beta (TGF-beta) type I receptor (ALK5) offer a novel approach for the treatment of fibrotic diseases such as renal, hepatic, and pulmonary fibrosis. The optimization of a novel phenylpyridine pyrazole series (1a) led to the identification of potent, selective, and orally active ALK5 inhibitors. The cellular potency and pharmacokinetics profiles of these derivatives were improved and several compounds presented antifibrotic activity when orally administered to rats in an acute liver model of dimethylnitrosamine- (DMN-) induced expression of collagen IA1 mRNA, a major gene contributing to excessive extra cellular matrix deposit. One of the most potent ALK5 inhibitors identified in this chemical series, compound 13d (GW788388), reduced the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). This compound significantly reduced the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis.
Asunto(s)
Receptores de Activinas Tipo I/antagonistas & inhibidores , Benzamidas/síntesis química , Pirazoles/síntesis química , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Enfermedad Aguda , Administración Oral , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Colágeno Tipo I/antagonistas & inhibidores , Colágeno Tipo I/biosíntesis , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Dimetilnitrosamina , Fibrosis , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Masculino , Modelos Moleculares , Proteínas Serina-Treonina Quinasas , Puromicina Aminonucleósido , Pirazoles/farmacocinética , Pirazoles/farmacología , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptor Tipo I de Factor de Crecimiento Transformador beta , Relación Estructura-ActividadRESUMEN
A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/enzimología , Lactamas/síntesis química , Lactamas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Serina Endopeptidasas/metabolismo , Animales , Antivirales/sangre , Disponibilidad Biológica , Encéfalo/metabolismo , Células Cultivadas , Perros , Diseño de Fármacos , Ensayo de Inmunoadsorción Enzimática , Ojo/metabolismo , Ganciclovir/farmacología , Cobayas , Semivida , Humanos , Indicadores y Reactivos , Cinética , Espectrometría de Masas , Modelos Moleculares , Inhibidores de Proteasas/sangre , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.v. clearance in the dog.
Asunto(s)
Lactamas/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Pirrolidinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Concentración 50 Inhibidora , Estructura Molecular , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
Asunto(s)
Diseño de Fármacos , Hepacivirus/enzimología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Estabilidad de Medicamentos , Hepacivirus/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Lactamas/síntesis química , Lactamas/farmacocinética , Lactamas/farmacología , Modelos Biológicos , Estructura Molecular , Inhibidores de Proteasas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Proteínas no Estructurales Virales/metabolismoRESUMEN
The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.