RESUMEN
A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Niacinamida/análogos & derivados , Pirazoles/química , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Remodelación Vascular/efectos de los fármacos , Administración por Inhalación , Animales , Línea Celular , Proliferación Celular , Hipertensión Pulmonar/patología , Pulmón/irrigación sanguínea , Membranas Artificiales , Simulación del Acoplamiento Molecular , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Niacinamida/síntesis química , Niacinamida/química , Niacinamida/farmacología , Permeabilidad , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/química , Pirazoles/síntesis química , Pirazoles/farmacología , Ratas , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/química , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/química , Receptores del Factor de Crecimiento Derivado de Plaquetas/química , Relación Estructura-ActividadRESUMEN
The four stereoisomers of mesoridazine were synthesized and evaluated in D2, 5-HT1A, 5-HT2A, 5-HT2C, D1, and D3 receptor binding and functional assays. Two isomers demonstrated potent D2 receptor binding (Ki < 3 nM) and functional antagonism (IC50 < or = 10 nM) activities. These two isomers also showed moderate affinity for the 5-HT2A and D3 receptors. A third isomer was devoid of significant D2 receptor binding, but did have moderate affinity for the 5-HT2A and D3 receptors. The fourth isomer demonstrated poor affinity for all the receptors tested. Most significantly, the stereochemistry of the sulfoxide moiety played a dominant role in the observed structure-activity relationship (SAR).