RESUMEN
The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor ß (THR-ß) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-ß selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-ß over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.
Asunto(s)
Descubrimiento de Drogas , Dislipidemias/tratamiento farmacológico , Piridazinas/síntesis química , Receptores beta de Hormona Tiroidea/agonistas , Uracilo/análogos & derivados , Animales , Densidad Ósea/efectos de los fármacos , Ensayos Clínicos como Asunto , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Piridazinas/metabolismo , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Uracilo/síntesis química , Uracilo/metabolismo , Uracilo/farmacología , Uracilo/uso terapéuticoRESUMEN
High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.
Asunto(s)
Diaminas/farmacología , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Diaminas/síntesis química , Diaminas/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.