RESUMO
Glycogen synthase kinase-3beta (GSK-3beta) is implicated in abnormal hyperphosphorylation of tau protein and its inhibitors are expected to be a promising therapeutic agents for the treatment of Alzheimer's disease. Here we report design, synthesis and structure-activity relationships of a novel series of oxadiazole derivatives as GSK-3beta inhibitors. Among these inhibitors, compound 20x showed highly selective and potent GSK-3beta inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of 20x and GSK-3beta.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Nitrilas/química , Nitrilas/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Benzimidazóis/síntese química , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Nitrilas/síntese química , Oxidiazóis/síntese química , Relação Estrutura-AtividadeRESUMO
Design, synthesis, and structure-activity relationships of thieno[2,3-b]pyridin-4-one-based non-peptide luteinizing hormone-releasing hormone (LHRH) receptor antagonists are described. Starting with the thienopyridin-4-one derivative 26d (T-98475) an optimization study was performed, which resulted in the identification of a highly potent and orally bioavailable LHRH receptor antagonist, 3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-2-[4-(1-hydroxy-1-cyclopropanecarboxamido)phenyl]-5-isobutyryl-4-oxothieno[2,3-b]pyridine (33c). Compound 33c displayed subnanomolar in vitro activities for the human receptor and its oral administration caused effective suppression of the plasma LH levels in castrated male cynomolgus monkeys. Furthermore, SAR studies revealed that a hydroxyalkylamido moiety on the 2-phenyl ring is virtually equivalent to an alkylureido moiety, at least in this series of compounds.
Assuntos
Piridinas/síntese química , Piridonas/síntese química , Receptores LHRH/antagonistas & inibidores , Tiofenos/síntese química , Administração Oral , Animais , Ácido Araquidônico/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca fascicularis , Masculino , Modelos Moleculares , Conformação Molecular , Piridinas/química , Piridinas/farmacologia , Piridonas/química , Piridonas/farmacologia , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
The design and synthesis of a new class of nonpeptide luteinizing hormone-releasing hormone (LHRH) receptor antagonists, the 2-phenylimidazo[1,2-a]pyrimidin-5-ones, is reported. Among compounds described in this study, we identified the potent antagonist 15b with nanomolar in vitro functional antagonism. The result might suggest that the heterocyclic 5-6-ring system possessing a pendant phenyl group attached to the five-membered ring is the important structural feature for a scaffold of small molecule LHRH antagonists.
