RESUMEN
P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM; P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).
Asunto(s)
Neuralgia/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X3/metabolismo , Triazinas/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Humanos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neuralgia/metabolismo , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Antagonistas del Receptor Purinérgico P2X/química , Ratas , Relación Estructura-Actividad , Triazinas/administración & dosificación , Triazinas/químicaRESUMEN
The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3, the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1, we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Pirazolonas/química , Pirazolonas/farmacología , Receptores Purinérgicos P2X3/metabolismo , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento Molecular , Pirroles/química , Pirroles/farmacología , Receptores Purinérgicos P2X3/química , Relación Estructura-ActividadRESUMEN
The P2X3 receptor is primarily expressed in the peripheral sensory nerves, and therefore, antagonists of this receptor may be useful for the treatment of chronic pain. Pyrrolinone derivatives have been identified as a novel class of P2X3 receptor antagonists. A lead structure with moderate activity was discovered through a high-throughput screening assay. A structure-activity study led to the discovery of several P2X3 receptor antagonists. Compound 34 showed potent and specific antagonistic activity and analgesic efficacy.