RESUMEN
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Asunto(s)
Bencimidazoles/farmacología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacocinética , Diseño de Fármacos , Células HEK293 , Humanos , Estructura Molecular , Solubilidad , Relación Estructura-Actividad , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinéticaRESUMEN
The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/química , Piperidinas/química , Piridinas/química , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Animales , Sitios de Unión , Perros , Semivida , Hepatocitos/metabolismo , Humanos , Infusiones Intravenosas , Concentración 50 Inhibidora , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/tratamiento farmacológico , Dolor/patología , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Unión Proteica , Estructura Terciaria de Proteína , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Tiadiazoles , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéuticoRESUMEN
Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.