RESUMEN
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Asunto(s)
Cognición/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Perros , Agonistas Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Asunto(s)
Cognición/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Conejos , Receptores Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
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
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Asunto(s)
Imidazolinas/farmacología , Antagonistas Purinérgicos/farmacología , Receptores Purinérgicos P2X7/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Haplorrinos , Imidazolinas/administración & dosificación , Imidazolinas/química , Imidazolinas/farmacocinética , Antagonistas Purinérgicos/administración & dosificación , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/farmacocinética , RatasRESUMEN
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
Asunto(s)
Analgésicos/síntesis química , Química Farmacéutica/métodos , Inflamación/tratamiento farmacológico , Ácidos Nicotínicos/síntesis química , Piridinas/síntesis química , Receptores de Prostaglandina E/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Diseño de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Ácidos Nicotínicos/farmacología , Piridinas/farmacología , Ratas , 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
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/metabolismo , Animales , Humanos , Enlace de Hidrógeno , Indoles/química , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Asunto(s)
Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Unión Proteica , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.