RESUMEN
The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.
Asunto(s)
Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Activadores de Enzimas/síntesis química , Activadores de Enzimas/farmacología , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Animales , Perros , Semivida , Humanos , Hipoglucemiantes/farmacología , Estructura Molecular , Piridinas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.
Asunto(s)
Amidas/química , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/química , Imidazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Línea Celular Tumoral , Química Física/métodos , Cristalografía por Rayos X , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/farmacología , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Imidazoles/farmacología , Infusiones Intravenosas , Modelos Químicos , Conformación Molecular , Trasplante de Neoplasias , Isoformas de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacologíaRESUMEN
The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model.
Asunto(s)
Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Glucoquinasa/metabolismo , Diseño de Fármacos , Activadores de Enzimas/farmacocinéticaRESUMEN
The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.
