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
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
Asunto(s)
Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Inhibidores de Fosfodiesterasa 4/farmacocinética , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Ratas , Solubilidad , Vómitos/tratamiento farmacológicoRESUMEN
The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.