RESUMEN
A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/análisis , Glucemia/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Secreción de Insulina , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Conformación Molecular , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11ß-HSD1. Among this series, 18e showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.