RESUMEN
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Asunto(s)
Pteridinas/química , Pirazinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Semivida , Pteridinas/síntesis química , Pteridinas/farmacocinética , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
Asunto(s)
Modelos Moleculares , Pteridinas/síntesis química , Piridazinas/síntesis química , Relación Estructura-Actividad Cuantitativa , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Plexo Coroideo/metabolismo , Lóbulo Frontal/metabolismo , Técnicas In Vitro , Pteridinas/química , Pteridinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , PorcinosRESUMEN
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
Asunto(s)
Pirazinas/síntesis química , Piridinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Animales , Ansiolíticos/síntesis química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Unión Competitiva , Perros , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Semivida , Técnicas In Vitro , Masculino , Pirazinas/farmacocinética , Pirazinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
The new Personal Chemistry ultralow-volume (0.2-0.5 mL) minivials are shown to enable small-scale optimization and synthesis of purines at optimal reaction concentrations (0.1-0.4 M), thereby increasing the overall efficiency of this microwave-assisted library synthesis.