RESUMEN
Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.
Asunto(s)
Aminopiridinas/farmacología , Bencimidazoles/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Neoplasias Encefálicas/patología , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Perros , Femenino , Glioblastoma/patología , Células de Riñón Canino Madin Darby , Masculino , Ratones , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Ratas , Temozolomida , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/química , Benzamidas/farmacología , Proteínas Sanguíneas/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Conformación Molecular , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/química , Piridinas/síntesis química , Piridinas/química , Quinuclidinas/farmacología , Ratas , Receptores Muscarínicos/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
Asunto(s)
Encéfalo/metabolismo , Diseño de Fármacos , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/química , Animales , Bungarotoxinas , Células Cultivadas , Electrofisiología , Potenciales Evocados Auditivos/efectos de los fármacos , Hipocampo/efectos de los fármacos , Activación del Canal Iónico/efectos de los fármacos , Estructura Molecular , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/química , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Trastornos del Conocimiento/tratamiento farmacológico , Agonistas Nicotínicos/síntesis química , Nootrópicos/síntesis química , Quinuclidinas/síntesis química , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Estabilidad de Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Potenciales Evocados Auditivos/efectos de los fármacos , Humanos , Técnicas In Vitro , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/fisiología , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacología , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Técnicas de Placa-Clamp , Quinuclidinas/química , Quinuclidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.