RESUMEN
Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell lines in vitro regardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved the in vitro metabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound to in vivo efficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes.
Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular , Diferenciación Celular , Piridinas/farmacologíaRESUMEN
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Asunto(s)
Antiinflamatorios/química , Isoindoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Células Sanguíneas/citología , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapéutico , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Isoindoles/farmacocinética , Isoindoles/uso terapéutico , Lipopolisacáridos/farmacología , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 µg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 µg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 µg/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 µg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 µg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.
Asunto(s)
Antifúngicos/farmacología , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/efectos de los fármacos , Azoles/farmacología , Sistema Enzimático del Citocromo P-450/genética , Proteínas Fúngicas/genética , Triazoles/farmacología , Administración Intranasal , Animales , Aspergillus fumigatus/aislamiento & purificación , Candida/efectos de los fármacos , Cryptococcus/efectos de los fármacos , Citocinas/sangre , Farmacorresistencia Fúngica , Células Epiteliales/metabolismo , Ergosterol/biosíntesis , Proteínas Fúngicas/antagonistas & inhibidores , Galactosa/análogos & derivados , Humanos , Hifa/metabolismo , Mananos/sangre , Ratones , Pruebas de Sensibilidad Microbiana , Rhizopus/efectos de los fármacos , Trichophyton/efectos de los fármacos , Voriconazol/farmacologíaRESUMEN
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Benzofuranos/química , Subtipo EP1 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Línea Celular , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Dolor/tratamiento farmacológico , Ratas , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Arginina/química , Etilaminas/química , Inhibidores de Proteasas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Etilaminas/síntesis química , Etilaminas/uso terapéutico , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.
Asunto(s)
Acetatos/química , Secretasas de la Proteína Precursora del Amiloide/fisiología , Piperidinas/química , Acetatos/metabolismo , Acetatos/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular Tumoral , Perros , Humanos , Ratones , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/metabolismo , Piperidinas/metabolismo , Piperidinas/farmacología , Ratas , Relación Estructura-Actividad , Especificidad por Sustrato/efectos de los fármacosRESUMEN
We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.
Asunto(s)
Aminopiridinas/uso terapéutico , Encéfalo/metabolismo , Morfolinas/uso terapéutico , Dolor/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Aminopiridinas/farmacocinética , Animales , Compuestos Aza , Células CHO , Línea Celular , Enfermedad Crónica , Cricetinae , Cricetulus , Descubrimiento de Drogas , Humanos , Indoles , Morfolinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Asunto(s)
Aminas/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Éteres/síntesis química , Pirimidinas/síntesis química , Sulfonas/síntesis química , Aminas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Farmacéutica/métodos , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Diseño de Fármacos , Éteres/farmacología , Humanos , Inflamación , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Enfermedades Neurodegenerativas/tratamiento farmacológico , Pirimidinas/farmacología , Ratas , Sulfonas/farmacologíaRESUMEN
Many years of work have been invested in the identification of potent and selective COX-2 inhibitors for the treatment of chronic inflammatory pain. One issue faced by workers is the balance between the lipophilicity required for potent enzyme inhibition and the physical properties necessary for drug absorption and distribution in vivo. Frequently approaches to reduce lipophilicity through introduction of polar functionality is hampered by highly challenging chemistry to prepare key molecules. We have complemented traditional synthetic chemistry with a biotransformations approach which efficiently provided access to an array of key target molecules.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/síntesis química , Biotransformación , Química Farmacéutica/métodos , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Diseño de Fármacos , Humanos , Inflamación/tratamiento farmacológico , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tiazinas/química , Administración Oral , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Simulación por Computador , Etilaminas/síntesis química , Etilaminas/química , Etilaminas/farmacología , Humanos , Ratones , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/farmacocinéticaRESUMEN
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Administración Oral , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Etilaminas/síntesis química , Etilaminas/farmacología , Humanos , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacologíaRESUMEN
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Disponibilidad Biológica , Perros , Etilaminas/síntesis química , Etilaminas/farmacocinética , Ratones , Ratones Noqueados , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
Asunto(s)
Analgésicos/síntesis química , Química Farmacéutica/métodos , Inflamación/tratamiento farmacológico , Ácidos Nicotínicos/síntesis química , Piridinas/síntesis química , Receptores de Prostaglandina E/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Diseño de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Ácidos Nicotínicos/farmacología , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
Asunto(s)
Analgésicos/síntesis química , Piridinas/síntesis química , Piridinas/uso terapéutico , Receptor Cannabinoide CB2/agonistas , Amidas/síntesis química , Amidas/farmacología , Amidas/uso terapéutico , Analgesia/métodos , Animales , Modelos Animales de Enfermedad , Descubrimiento de Drogas/métodos , Inflamación , Dolor/tratamiento farmacológico , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Asunto(s)
Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piridinas/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Piridinas/química , Piridinas/uso terapéutico , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
Asunto(s)
Encéfalo/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Pirazoles/química , Receptores de Prostaglandina E/antagonistas & inhibidores , Amidas/química , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Isoquinolinas/química , Modelos Químicos , Estructura Molecular , Subtipo EP1 de Receptores de Prostaglandina E , Solubilidad , Relación Estructura-ActividadRESUMEN
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Analgésicos/química , Animales , Encéfalo/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estructura Molecular , Dimensión del Dolor , Pirazoles/química , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Benzotiadiazinas/síntesis química , Óxidos S-Cíclicos/síntesis química , Etilaminas/síntesis química , Administración Oral , Animales , Benzotiadiazinas/farmacocinética , Benzotiadiazinas/farmacología , Disponibilidad Biológica , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/farmacología , Perros , Etilaminas/farmacocinética , Etilaminas/farmacología , Modelos Moleculares , Ratas , Relación Estructura-ActividadRESUMEN
The possible neuroprotective role of a novel and highly selective cyclooxygenase-2 inhibitor GW637185X was studied in a model of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced injury of nigrostriatal dopaminergic (DA) neurons in the mouse. Stereological and microdensitometrical analysis of nigral tyrosine hydroxylase-immunoreactive cell bodies and striatal tyrosine hydroxylase-immunoreactive terminals, respectively, showed that GW637185X exerted a full protection against MPTP-induced degeneration of the nigro-striatal pathway. In contrast to earlier studies, these findings demonstrate that acute inhibition of cyclooxygenase-2 can result in a full neuroprotective effect not only on nigral DA cell bodies, but also on striatal DA terminals in the mouse MPTP model.
Asunto(s)
Encéfalo/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Intoxicación por MPTP/tratamiento farmacológico , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Dopamina/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/inducido químicamente , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.