RESUMO
AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzoxazinone derivatives with good to very good in vitro activity as positive allosteric AMPAR modulators was synthesized and evaluated. The appropriate substituent choice on the benzoxazinone fragment improved the affinity towards the AMPA receptor significantly in comparison to our lead molecule CX614.
Assuntos
Benzoxazinas/química , Receptores de AMPA/efeitos dos fármacos , Regulação Alostérica , Animais , Benzoxazinas/farmacologia , Estrutura Molecular , Prosencéfalo/efeitos dos fármacos , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The structure-based design, synthesis, and biological activity of novel inhibitors of S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Using 6-substituted purine and deaza purines as the core scaffolds, a systematic and structure guided series of modifications provided low nM inhibitors with broad-spectrum antimicrobial activity.
Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , N-Glicosil Hidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Homocisteína/antagonistas & inibidores , Homocisteína/metabolismo , N-Glicosil Hidrolases/metabolismo , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/metabolismo , Purinas/síntese química , Purinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.