RESUMEN
NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration.
Asunto(s)
Antineoplásicos/farmacología , Axones/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Axones/metabolismo , Axones/patología , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Sistema Enzimático del Citocromo P-450/metabolismo , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Nicotinamida Fosforribosiltransferasa/metabolismo , Relación Estructura-ActividadRESUMEN
A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Indoles/química , Indoles/uso terapéutico , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Xenoinjertos , Humanos , Indoles/farmacocinética , Masculino , Ratones , Ratones Desnudos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Microtúbulos/patología , Trasplante de Neoplasias , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/ultraestructura , Moduladores de Tubulina/farmacocinéticaRESUMEN
In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10 mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation.
Asunto(s)
Descubrimiento de Drogas , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Encéfalo/irrigación sanguínea , Células HEK293 , Humanos , Ligandos , Trastornos Migrañosos/tratamiento farmacológico , Modelos Moleculares , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus-pituitary-adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling.
Asunto(s)
Encéfalo/metabolismo , Regulación de la Expresión Génica , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Encéfalo/embriología , Encéfalo/fisiología , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Dexametasona/farmacología , Hipocampo/metabolismo , Ligandos , Masculino , Mifepristona/farmacología , Coactivador 1 de Receptor Nuclear/metabolismo , Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Esteroides/metabolismo , Factores de Tiempo , Transcripción Genética , Técnicas del Sistema de Dos HíbridosRESUMEN
The identification and hit-to-lead exploration of a novel, potent and selective series of histamine H(4) receptor inverse agonists is described. The initial hit, 3A (IC(50) 19 nM) was identified by means of a ligand-based virtual screening approach. Subsequent medicinal chemistry exploration yielded 18I which possessed increased potency (R-enantiomer IC(50) 1 nM) as well as enhanced microsomal stability.
Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Concentración 50 Inhibidora , Macaca fascicularis , Ratas , Receptores Histamínicos , Receptores Histamínicos H4 , EstereoisomerismoRESUMEN
The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.
Asunto(s)
Benceno/química , Hidrógeno/química , Isoquinolinas/química , Isoquinolinas/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Azufre/química , Isoquinolinas/síntesis química , Estructura Molecular , Unión Proteica , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antidepresivos/síntesis química , Glucocorticoides/química , Receptores de Glucocorticoides/metabolismo , Animales , Antidepresivos/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Cinética , Modelos Químicos , Conformación Molecular , Ratas , Receptores de Esteroides/metabolismo , Relación Estructura-ActividadRESUMEN
Further investigation of a series of thienyl-based hydroxamic acids that included ADS100380 and ADS102550 led to the identification of the 5-pyridin-2-yl-thiophene-2-hydroxamic acid 3c, which possessed modest HDAC inhibitory activity. Substitution at the 5- and 6-positions of the pyridyl ring of compound 3c provided compounds 5a-g, 7a, b, 9, and 13a. Compound 5b demonstrated improved potency, in vitro DMPK profile, and rat oral bioavailability, compared to ADS102550. Functionalisation of the pendent phenyl group of compounds 5b, 5e and 13a provided analogues that possessed excellent enzyme inhibition and anti-proliferative activity.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Disponibilidad Biológica , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacocinética , Humanos , Indicadores y Reactivos , Inyecciones Intravenosas , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Humanos , Indicadores y Reactivos , Ratones , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
We have modified the previously reported 2-aminoquinoline 1 to provide two novel series of MCH-1R antagonists. Representative compounds from the quinazoline and benzimidazole series have been shown to be potent and selective, with promising in vitro eADME profiles.
Asunto(s)
Bencimidazoles/síntesis química , Quinazolinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Bencimidazoles/farmacología , Humanos , Concentración 50 Inhibidora , Unión Proteica , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
Melanin-concentrating hormone (MCH) has been known to be an appetite-stimulating peptide for a number of years. However, it is only recently that MCH has been discovered to be the natural ligand for a previously "orphan" G-protein-coupled receptor, now designated MCH-1R. This receptor has been shown to mediate the effects of MCH on appetite and body weight, and consequently, drug discovery programs have begun to exploit this information in the search for MCH-1R antagonists for the treatment of obesity. In this paper, we report the rapid discovery of multiple, structurally distinct series of MCH-1R antagonists using a variety of virtual screening techniques. The most potent of these compounds (12) demonstrated an IC(50) value of 55 nM in the primary screen and exhibited antagonist properties in a functional cellular assay measuring Ca(2+) release. More potent compounds were identified by follow-up searches around the initial hit. A proposed binding mode for compound 12 in a homology model of the MCH-1R is also presented.