RESUMO
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.
Assuntos
Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hipoglicemiantes/química , Animais , Cães , Meia-Vida , Humanos , Hipoglicemiantes/farmacologia , Estrutura Molecular , Piridinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Ativadores de Enzimas/química , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Desenho de Fármacos , Ativadores de Enzimas/farmacocinéticaRESUMO
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.