RESUMO
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Assuntos
Benzopiranos/química , Inibidores Enzimáticos/química , Esterases/antagonistas & inibidores , Animais , Benzopiranos/farmacocinética , Benzopiranos/uso terapêutico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Esterases/metabolismo , Fêmur/fisiologia , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of potent piperidine-linked cytosine derivatives were prepared as inhibitors of deoxycytidine kinase (dCK). Compound 9h was discovered to be a potent inhibitor of dCK and shows a good combination of cellular potency and pharmacokinetic parameters. Compound 9h blocks the incorporation of radiolabeled cytosine into mouse T-cells in vitro, as well as in vivo in mice following a T-cell challenge.
Assuntos
Desoxicitidina Quinase/antagonistas & inibidores , Flucitosina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Desenho de Fármacos , Flucitosina/síntese química , Flucitosina/química , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.