RESUMEN
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.
Asunto(s)
Aminopiridinas/química , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Administración Oral , Aminopiridinas/metabolismo , Aminopiridinas/uso terapéutico , Animales , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/antagonistas & inhibidores , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eliminación de Gen , Semivida , Humanos , Unión Proteica , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
Asunto(s)
Indolizinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Células CHO , Cricetinae , Cricetulus , Dermatitis por Contacto/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Semivida , Humanos , Hipersensibilidad/tratamiento farmacológico , Indolizinas/farmacocinética , Indolizinas/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Relación Estructura-Actividad , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
A novel and robust synthesis of the fragment, 2-amino-5-tert-butylpyridine, has been described, which has been shown to have improved physicochemical properties over 4-tert-butylaniline, when considering drug-like properties. The synthesis also yields fragments containing more highly oxidised precursors to the tert-butyl group as intermediates. These fragments can be incorporated into final target molecules, yielding pharmaceutical compounds and their putative CYP-mediated oxidative metabolites, which can aid in elucidation of metabolic clearance processes.