RESUMO
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.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Pirimidinas/química , Triazóis/química , Animais , Sítios de Ligação , Encéfalo/metabolismo , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Termodinâmica , Triazóis/metabolismo , Triazóis/farmacocinéticaRESUMO
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 The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus.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.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Indóis/síntese química , Desenho de Fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
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.