RESUMEN
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Asunto(s)
Analgésicos/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Analgésicos/síntesis química , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Adyuvante de Freund/farmacología , Humanos , Hiperalgesia/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/uso terapéutico , Ratas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismoRESUMEN
This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.
Asunto(s)
Sitio Alostérico , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Piridinas/química , Animales , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Perros , Humanos , Masculino , Tasa de Depuración Metabólica , Estructura Molecular , Neoplasias de la Próstata/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-Actividad , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Células Tumorales CultivadasRESUMEN
This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Relación Estructura-Actividad , Ligando Inductor de Apoptosis Relacionado con TNF/farmacologíaRESUMEN
Syntheses of the eight enantiomerically pure diastereomers of the 12-F(2)-isoprostanes (4-11) are described. The key steps included rhodium-mediated intramolecular cyclopropanation and enzymatic resolution of the racemic diol 12.