RESUMEN
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Asunto(s)
Antiinflamatorios/química , Isoindoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Células Sanguíneas/citología , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapéutico , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Isoindoles/farmacocinética , Isoindoles/uso terapéutico , Lipopolisacáridos/farmacología , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Benzofuranos/química , Subtipo EP1 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Línea Celular , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Dolor/tratamiento farmacológico , Ratas , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Asunto(s)
Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piridinas/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Piridinas/química , Piridinas/uso terapéutico , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
Asunto(s)
Glicinérgicos/síntesis química , Glicinérgicos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Células CHO , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Dinoprostona/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Indicadores y Reactivos , Subtipo EP1 de Receptores de Prostaglandina ERESUMEN
The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.
Asunto(s)
Inhibidores de la Ciclooxigenasa/uso terapéutico , Hidrocarburos Aromáticos/uso terapéutico , Nitrógeno/uso terapéutico , Dolor/tratamiento farmacológico , Animales , Encéfalo/metabolismo , Células COS , Capsaicina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Hidrocarburos Aromáticos/farmacocinética , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones , Nitrógeno/farmacocinética , Pirazoles , Piridazinas , RatasRESUMEN
GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.