RESUMEN
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Asunto(s)
Benzamidas/uso terapéutico , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB2/metabolismo , Sulfonamidas/uso terapéutico , Animales , Benzamidas/síntesis química , Benzamidas/farmacología , Sitios de Unión , Relación Dosis-Respuesta a Droga , Ligandos , Ratones , Modelos Animales , Modelos Químicos , Dimensión del Dolor/efectos de los fármacos , Ratas , Receptor Cannabinoide CB2/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
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
Synthesis, in vitro biological evaluation, and structure-activity relationships of a biaryl cannabinoid mimetic 2 are reported. Variations in the substitution pattern yielded a number of agonists with low nanomolar affinity. Replacing the phenol group by a methyl morpholino acetate group led to compound 28, a 500-fold selective CB(2) receptor agonist.
Asunto(s)
Cannabinoides/química , Cannabinoides/síntesis química , Química Farmacéutica/métodos , Ácidos Carboxílicos/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Hidrógeno/química , Enlace de Hidrógeno , Inmunosupresores/química , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Parasimpatolíticos , Fenol/química , Unión ProteicaRESUMEN
10-Hydroxy-10,9-boroxarophenanthrenes were obtained as unexpected major products upon BBr(3)-mediated O-demethylation of 2-methoxybiaryls. The formation likely proceeds via intramolecular electrophilic aromatic cyclization of a reactive dibromoaryloxyborane intermediate. Essentially quantitative yields of 10-hydroxy-10,9-boroxarophenanthrenes were also obtained from 2-hydroxybiaryl and BCl(3)/AlCl(3) with use of a modified literature procedure. As synthetic intermediates, 10-hydroxy-10,9-boroxarophenanthrenes were efficiently converted to 3,4-benzocoumarins and triaryls through Pd-catalyzed CO insertion and Suzuki reaction.