RESUMEN
Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27.
RESUMEN
The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.
Asunto(s)
Complemento C5/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Complemento C5/metabolismo , Humanos , Conformación Molecular , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.
Asunto(s)
Amidas/farmacología , Ciclopropanos/farmacología , Citocinas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Adenosina/análogos & derivados , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Ciclopropanos/síntesis química , Ciclopropanos/química , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Nicotinamida Fosforribosiltransferasa/metabolismo , Fenotipo , Relación Estructura-ActividadRESUMEN
Although cycloadditions of azomethine ylides usually give mixtures of endo/exo adducts, we successfully tuned the mechanistic path of a new reaction cascade to afford substituted pyrrolidines in high yields and diastereomeric purity. This was achieved by forcing the demetalation of tin- or silicon-substituted iminium ions, followed by azomethine ylide cycloaddition and nucleophilic cyclization. Structural complexity is thus built rapidly in a fully controlled one-pot reaction cascade.
Asunto(s)
Compuestos Azo/química , Pirrolidinas/síntesis química , Tiosemicarbazonas/química , Ciclización , Estructura Molecular , Pirrolidinas/química , EstereoisomerismoRESUMEN
Although ketone enamines are widely used in organic synthesis, aldehyde enamines are rarely employed due to the limitations of their preparation using known methods (need for acid or base, excess of amine, and/or elevated temperature). We have successfully developed rapid and particularly mild condensation conditions (1 h, 0 degrees C, 1.2 equiv of amine) leading to di- and trisubstituted enamines with excellent conversion (84-100%). Remarkably high chemoselectivity was observed with complete discrimination between aldehyde and ketone, among other functional groups positively tested.
