RESUMEN
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tiofenos/química , Administración Oral , Animales , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Pirimidinonas/síntesis química , Pirimidinonas/uso terapéutico , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/uso terapéuticoRESUMEN
Novel P2X(7) antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X(7) receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure-activity relationship (SAR) development and results of pain models are presented.
Asunto(s)
Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/síntesis química , Purinas/síntesis química , Receptores Purinérgicos P2X7/química , Animales , Humanos , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Purinas/química , Purinas/uso terapéutico , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X(7) receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
Asunto(s)
Analgésicos/síntesis química , Diseño de Fármacos , Dolor , Antagonistas del Receptor Purinérgico P2/síntesis química , Administración Oral , Analgésicos/química , Animales , Modelos Animales de Enfermedad , Humanos , Estructura Molecular , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2/química , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R=H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure-activity relationship (SAR) of these and related compounds are discussed.
Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores Opioides/efectos de los fármacos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Sitios de Unión , Capsaicina/farmacología , Técnicas Químicas Combinatorias , Tos/inducido químicamente , Modelos Animales de Enfermedad , Diseño de Fármacos , Cobayas , Estructura Molecular , Piperidinas/química , Receptores Opioides/metabolismo , Compuestos de Espiro/química , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A series of N-substituted analogs based upon the spiropiperidine core of 1 was synthesized and exhibited high binding affinity to the nociceptin (NOP) receptor. The selectivities against other known opioid receptors were determined.
Asunto(s)
Piperidinas/síntesis química , Receptores Opioides/agonistas , Administración Oral , Animales , Tos/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Guanosina 5'-O-(3-Tiotrifosfato) , Ligandos , Farmacocinética , Piperidinas/farmacocinética , Piperidinas/farmacología , Unión Proteica , Ratas , Receptores Opioides/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Fármacos Neuroprotectores/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Antagonistas del Receptor de Adenosina A1 , Fenómenos Químicos , Química Física , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Relación Estructura-ActividadRESUMEN
The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A(2A) receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Pirimidinas/farmacología , Triazoles/farmacología , Administración Oral , Animales , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Masculino , Estructura Molecular , Pirimidinas/química , Pirimidinas/clasificación , Pirimidinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Pirimidinas/farmacología , Triazoles/farmacología , Administración Oral , Animales , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Actividad Motora/efectos de los fármacos , Pirimidinas/química , Pirimidinas/clasificación , Pirimidinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor.
