RESUMEN
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/farmacología , Analgésicos/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzopiranos/administración & dosificación , Benzopiranos/química , Células CHO , Ensayos Clínicos como Asunto , Cricetinae , Cricetulus , Cristalografía por Rayos X , Inhibidores del Citocromo P-450 CYP2D6 , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/químicaRESUMEN
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Administración Oral , Analgésicos/síntesis química , Analgésicos/química , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzopiranos/síntesis química , Benzopiranos/química , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Dosis Máxima Tolerada , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Ratas , Pruebas de ToxicidadRESUMEN
A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, mu opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective mu opioid receptor antagonist, which interacts selectively with mu peripheral receptors.
