RESUMEN
We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC50's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 ± 0.39 nM, â¼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/química , Pirimidinas/química , Triazoles/química , Animales , Sitios de Unión , Encéfalo/metabolismo , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Diseño de Fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Termodinámica , Triazoles/metabolismo , Triazoles/farmacocinéticaRESUMEN
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Indoles/síntesis química , Diseño de Fármacos , Humanos , Relación Estructura-ActividadRESUMEN
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.