RESUMEN
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
Asunto(s)
Antineoplásicos/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Quinolizinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/síntesis química , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/farmacocinética , Perros , Descubrimiento de Drogas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Quinolizinas/síntesis química , Quinolizinas/metabolismo , Quinolizinas/farmacocinética , Células RAW 264.7 , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To mimic amphiphilic alpha-helices, a new scaffold was designed based on a bis-benzamide that places four side-chain functional groups found at the i, i+2, i+5, and i+7 positions of a helix. Its two hydrogen bonds fix the conformation and provide accurate bifacial arrangement of the four substituents, simultaneously representing two opposing helical sides. An efficient synthetic route was achieved for the construction of bis-benzamides, and their superior alpha-helix mimicry was confirmed by X-ray crystallography.
Asunto(s)
Benzamidas/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura MolecularRESUMEN
The Ir-catalyzed enantioselective hydrogenation of various N-(3,5-dimethyl-4-methoxy)phenylimines was performed under mild conditions in the presence of new P,N-ferrocenyl iridium complexes leading to (R)-N-(3,5-dimethyl-4-methoxy)phenylamines in high yields and enantioselectivities (up to 99%). These chiral aryl amines can be readily deprotected using Ce(NH4)2(NO3)6.
