RESUMEN
Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3ß-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3ß/GSK-3α) GSK-3ß inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/ß-catenin signaling activation, was observed in cells.
Asunto(s)
Encéfalo/metabolismo , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Tomografía de Emisión de Positrones/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagen , Dominio Catalítico , Glucógeno Sintasa Quinasa 3 beta/química , Células HEK293 , Humanos , Ratones , Modelos Moleculares , Neuroimagen , Oxazoles/química , Oxazoles/metabolismo , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/metabolismo , Triazoles/química , Triazoles/metabolismo , Triazoles/farmacologíaRESUMEN
A mild Ru/Ni dual catalytic desulfinative photoredox Csp2-Csp3 cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru(bpy)3Cl2, Ni(COD)2, and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the Csp2-Csp3 cross-coupling reaction allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues via a parallel medicinal chemistry effort.
RESUMEN
Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation inâ vitro and inâ vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Neuroimagen , Oxazoles/farmacología , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/farmacología , Triazoles/farmacología , Proteínas tau/antagonistas & inhibidores , Encéfalo/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Oxazoles/síntesis química , Oxazoles/química , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Triazoles/síntesis química , Triazoles/química , Proteínas tau/metabolismoRESUMEN
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.
Asunto(s)
Infección Hospitalaria/tratamiento farmacológico , Descubrimiento de Drogas , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Polimixinas/química , Polimixinas/farmacología , beta-Alanina/análogos & derivados , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/toxicidad , Perros , Femenino , Bacterias Gramnegativas/fisiología , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Polimixinas/farmacocinética , Polimixinas/toxicidad , Ratas , beta-Alanina/químicaRESUMEN
A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2Å resolution).
Asunto(s)
Antibacterianos/química , Eritromicina/análogos & derivados , Compuestos de Metilurea/química , Staphylococcus/aislamiento & purificación , Streptococcus/aislamiento & purificación , Antibacterianos/síntesis química , Sitios de Unión , Cristalografía por Rayos X , Deinococcus/metabolismo , Farmacorresistencia Bacteriana , Eritromicina/síntesis química , Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Terciaria de Proteína , Pirrolidinas/química , Subunidades Ribosómicas Grandes Bacterianas/química , Subunidades Ribosómicas Grandes Bacterianas/metabolismo , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacosRESUMEN
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Ácidos Hidroxámicos/síntesis química , Piridonas/síntesis química , Ácidos Sulfónicos/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cristalografía por Rayos X , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácidos Sulfónicos/farmacocinética , Ácidos Sulfónicos/farmacologíaRESUMEN
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.