RESUMEN
Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.
Asunto(s)
Aminoquinolinas/química , Diseño de Fármacos , Proteínas/metabolismo , Administración Oral , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Aminoquinolinas/uso terapéutico , Animales , Benzoatos/química , Benzoatos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Semivida , Humanos , Masculino , Ratones , Conformación Molecular , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Ratas , Relación Estructura-ActividadRESUMEN
A highly efficient tandem double Friedel-Crafts reaction between indoles and 2-formylbiphenyl derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl) fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products with opposite absolute configuration.