RESUMEN
We have identified short N,C-capped peptides that selectively inhibit the proteasome of the malaria-causing pathogen Plasmodium falciparum. These compounds are highly potent in culture with no toxicity in host cells. One cyclic biphenyl ether compound inhibited intraerythrocytic growth of P. falciparum with an IC50 of 35 nM, and we show that even a pulse treatment with this cyclic peptide induced parasite death due to proteasome inhibition. These compounds represent promising new antimalarial agents that target the essential proteasomal machinery of the parasite without toxicity toward the host.
Asunto(s)
Antimaláricos/farmacología , Péptidos Cíclicos/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Antimaláricos/química , Antimaláricos/toxicidad , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Péptidos Cíclicos/química , Péptidos Cíclicos/toxicidad , Plasmodium falciparum/crecimiento & desarrollo , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/toxicidadRESUMEN
Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibitors. Constrained heterocyclic analogs based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine show further enhanced HDAC6 selectivity and inhibitory activity in cells. Homology models suggest that the heterocyclic spacer can more effectively access the wider catalytic channel of HDAC6 compared to other HDAC sub-types.
Asunto(s)
Inhibidores de Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/farmacología , Pirazinas/metabolismo , Isoformas de ProteínasRESUMEN
We identified N,C-capped dipeptides that are selective for the Mycobacterium tuberculosis proteasome over human constitutive and immunoproteasomes. Differences in the S3 and S1 binding pockets appeared to account for the species selectivity. The inhibitors can penetrate mycobacteria and kill nonreplicating M. tuberculosis under nitrosative stress.
Asunto(s)
Dipéptidos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Sitios de Unión/efectos de los fármacos , Dipéptidos/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/química , Relación Estructura-ActividadRESUMEN
The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.
Asunto(s)
Oligopéptidos/farmacología , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasoma , Secuencia de Aminoácidos , Sitios de Unión , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Células HCT116 , Células HT29 , Humanos , Cinética , Luciferasas/genética , Luciferasas/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , FN-kappa B/genética , FN-kappa B/metabolismo , Oligopéptidos/química , Oligopéptidos/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Pirazinas/farmacología , Interferencia de ARN , Homología de Secuencia de Aminoácido , Ubiquitina/genética , Ubiquitina/metabolismoRESUMEN
A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/química , Piridinas/química , Sustitución de Aminoácidos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the ß-5/6 active site of y20S. Derivative 25, (ß5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.
Asunto(s)
Quimotripsina/antagonistas & inhibidores , Dipéptidos/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Treonina/química , Humanos , Modelos MolecularesRESUMEN
The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/química , Sustitución de Aminoácidos , Sitios de Unión , Simulación por Computador , Evaluación Preclínica de Medicamentos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacocinética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8 antagonists is described. In vitro binding assay results of these investigations are reported, critical interactions of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for the naphthalene scaffold are presented.
Asunto(s)
Naftalenos/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Sulfonamidas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Transporte Biológico , Calcio/metabolismo , Línea Celular , Cricetinae , Cricetulus , Diseño de Fármacos , Humanos , Naftalenos/farmacocinética , Naftalenos/farmacología , Ratas , Receptores CCR8 , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
Asunto(s)
Cumarinas/síntesis química , Piperidinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cumarinas/efectos adversos , Cumarinas/farmacología , Perros , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Humanos , Masculino , Ratones , Ratones Obesos , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Benzamidas/química , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/síntesis química , Humanos , Especificidad por SustratoRESUMEN
Reductive aminations and further transformations of an azo dye and fluorous tagged aldehyde are described. The intensely colored 2,4-dialkoxybenzyl protected amines undergo Fmoc-based peptide coupling, Suzuki reactions, and sulfonamide formation with product isolation facilitated by visual monitoring of fluorous solid phase extraction. Target compounds are released from the supports in high yields and purities by treatment with trifluoroacetic acid (TFA).
Asunto(s)
Compuestos Cromogénicos/química , Flúor/química , Compuestos Azo/química , Estructura Molecular , Extracción en Fase Sólida , Ácidos Sulfínicos/químicaRESUMEN
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Ratones , Ratones Desnudos , Modelos Moleculares , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.
Asunto(s)
Quinazolinas/química , Quinazolinas/farmacología , Quinolonas/química , Quinolonas/farmacología , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Ratones , Quinazolinas/farmacocinética , Quinolonas/farmacocinéticaRESUMEN
The identification and optimization of a series of acylguanidine-based melanocortin-4 receptor antagonists is discussed.
Asunto(s)
Guanidina/química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Compuestos de Sulfhidrilo/química , Animales , Sitios de Unión , Encéfalo/metabolismo , Guanidina/análogos & derivados , Guanidina/farmacología , Concentración 50 Inhibidora , Ratones , Plasma/metabolismo , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/farmacología , Factores de TiempoRESUMEN
Several potent, cell permeable 4-aryl-dihydropyrimidinones have been identified as inhibitors of FATP4. Lipophilic ester substituents at the 5-position and substitution at the para-position (optimal groups being -NO(2) and CF(3)) of the 4-aryl group led to active compounds. In two cases racemates were resolved and the S enantiomers shown to have higher potencies.
Asunto(s)
Proteínas de Transporte de Ácidos Grasos/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Línea Celular , Humanos , Estructura Molecular , Pirimidinonas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] Reaction of o-azidobenzenesulfonamides with polymer-supported triphenylphosphine affords the corresponding iminophosphoranes. Subsequent reaction with isocyanates gives 3-amino-1,2,4-benzothiadiazine 1,1-dioxides in high yields and purities. The reaction has been successfully applied to the synthesis of derivatives with various substituents at the 2- and 3-positions and in the benzenoid ring.
Asunto(s)
Azidas/química , Isocianatos/química , Compuestos Organofosforados/química , Sulfonamidas/química , Triazinas/síntesis química , Ciclización , Estructura Molecular , Estereoisomerismo , Tirapazamina , Triazinas/químicaRESUMEN
The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Benzamidas/química , Benzamidas/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/síntesis química , Benzamidas/síntesis química , Unión Competitiva , Modelos Animales de Enfermedad , Perros , Ratones , Estructura Molecular , Piperidinas/síntesis química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50.
Asunto(s)
Niacinamida/análogos & derivados , Receptores de Somatostatina/antagonistas & inhibidores , ortoaminobenzoatos/síntesis química , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Benzamidas/farmacología , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos , Niacinamida/farmacocinética , Niacinamida/farmacología , Farmacocinética , Receptores de Somatostatina/agonistas , Relación Estructura-Actividad , Distribución Tisular , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologíaRESUMEN
A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.