RESUMEN
Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
Asunto(s)
Aminopiridinas/uso terapéutico , Antiinflamatorios/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Inflamación/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Aminopiridinas/síntesis química , Aminopiridinas/farmacocinética , Aminopiridinas/toxicidad , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Antiinflamatorios/toxicidad , Femenino , Humanos , Estructura Molecular , Nivel sin Efectos Adversos Observados , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/toxicidad , Pirazinas/síntesis química , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Pirazinas/toxicidad , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.