RESUMEN
Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure-activity relationship (SAR) trends observed.
Asunto(s)
Antivirales/química , Descubrimiento de Drogas/métodos , Imidazolidinas/química , Indoles/química , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Inhibidores de Proteínas Virales de Fusión/química , Administración Oral , Antivirales/administración & dosificación , Cristalografía por Rayos X/métodos , Células HeLa , Humanos , Imidazolidinas/administración & dosificación , Indoles/administración & dosificación , Estructura Secundaria de Proteína , Virus Sincitial Respiratorio Humano/fisiología , Inhibidores de Proteínas Virales de Fusión/administración & dosificaciónRESUMEN
In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Diseño de Fármacos , Indoles/síntesis química , Indoles/farmacología , Proteínas Virales/efectos de los fármacos , Células A549 , Animales , Antivirales/química , Antivirales/farmacocinética , Cristalografía por Rayos X , Perros , Humanos , Indoles/química , Indoles/farmacocinética , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Células de Riñón Canino Madin Darby , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
The synthesis, SAR and preclinical characterization of a series of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca(2+) flux and whole blood IL-1ß P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1ß release in a mouse ex vivo model with a 50mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects.
