RESUMEN
The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.
Asunto(s)
Síndrome Torácico Agudo , Anemia de Células Falciformes , Síndrome Torácico Agudo/tratamiento farmacológico , Síndrome Torácico Agudo/etiología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Niño , Hemorragia/tratamiento farmacológico , Humanos , Dolor/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , Ticagrelor/uso terapéuticoAsunto(s)
Alopurinol , Quimioterapia Combinada , Insuficiencia Renal Crónica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alopurinol/uso terapéutico , Alopurinol/administración & dosificación , Método Doble Ciego , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicacionesRESUMEN
Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.
Asunto(s)
Atorvastatina/farmacocinética , Piridonas/farmacocinética , Triazoles/farmacocinética , Adulto , Área Bajo la Curva , Atorvastatina/sangre , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridonas/sangre , Inhibidores de la Transcriptasa Inversa/farmacocinética , Triazoles/sangreRESUMEN
The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Asunto(s)
Carbamatos/química , Oxazolidinonas/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/química , Esquizofrenia/tratamiento farmacológico , Administración Oral , Regulación Alostérica , Sitio Alostérico , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Microsomas/metabolismo , Modelos Químicos , Estructura Molecular , Oxazolidinonas/químicaRESUMEN
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
Asunto(s)
Regulación Alostérica , Compuestos de Azabiciclo/síntesis química , Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Éteres/química , Receptores de Glutamato Metabotrópico/química , Administración Oral , Sitio Alostérico , Animales , Compuestos de Azabiciclo/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Microsomas/efectos de los fármacos , Modelos Químicos , Ratas , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Animales , Disponibilidad Biológica , Encéfalo/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacocinética , Imidazoles/farmacología , Concentración 50 Inhibidora , Memoria a Corto Plazo/efectos de los fármacos , Simulación del Acoplamiento Molecular , Conformación ProteicaRESUMEN
Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Perros , Haplorrinos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacocinética , RatasRESUMEN
Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2,3-d]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2,3-d]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrinmidin-2-one analogues.
Asunto(s)
Cobre/química , Pirimidinonas/síntesis química , Uracilo/síntesis química , Catálisis , Pirimidinonas/química , Uracilo/análogos & derivados , Uracilo/químicaRESUMEN
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
Asunto(s)
Antipsicóticos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Imidazoles/síntesis química , Piperidinas/síntesis química , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Perros , Humanos , Hipercinesia/inducido químicamente , Hipercinesia/tratamiento farmacológico , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Metanfetamina , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacología , Conformación Proteica , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Nootrópicos/síntesis química , Nootrópicos/farmacología , Oxazoles/síntesis química , Oxazoles/farmacología , Receptores Nicotínicos/química , Esquizofrenia/tratamiento farmacológico , Animales , Compuestos de Azabiciclo/química , Disponibilidad Biológica , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Agonistas Nicotínicos/química , Nootrópicos/química , Oocitos/efectos de los fármacos , Oxazoles/química , Ratas , Piel/citología , Piel/efectos de los fármacos , Relación Estructura-Actividad , Xenopus laevis/crecimiento & desarrollo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.