RESUMEN
Whereas treatment of allergic diseases such as asthma relies largely on the targeting of dysregulated effector pathways, the conceptually attractive alternative of preventing them by a pharmaceutical, at-source intervention has been stymied until now by uncertainties about suitable targets and the challenges facing drug design. House dust mites (HDMs) are globally significant triggers of allergy. Group 1 HDM allergens, exemplified by Der p 1, are cysteine proteases. Their degradome has a strong disease linkage that underlies their status as risk and initiator allergens acting directly and through bystander effects on other allergens. Our objective was to test whether target-selective inhibitors of group 1 HDM allergens might provide a viable route to novel therapies. Using structure-directed design to optimize a series of pyruvamides, we undertook the first examination of whether pharmaceutically developable inhibitors of group 1 allergens might offer protection against HDM exposure. Developability criteria included durable inhibition of clinically relevant signals after a single aerosolized dose of the drug. The compounds suppressed acute airway responses of rats and mice when challenged with an HDM extract representing the HDM allergome. Inhibitory effects operated through a miscellany of downstream pathways involving, among others, IL-33, thymic stromal lymphopoietin, chemokines, and dendritic cells. IL-13 and eosinophil recruitment, indices of Th2 pathway activation, were strongly attenuated. The surprisingly expansive benefits arising from a unique at-source intervention suggest a novel approach to multiple allergic diseases in which HDMs play prominent roles and encourage exploration of these pharmaceutically developable molecules in a clinical setting.
RESUMEN
Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.
Asunto(s)
Benzoxazinas/síntesis química , Benzoxazinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirazoles/síntesis química , Pirazoles/farmacología , Administración Oral , Animales , Benzoxazinas/química , Técnicas Químicas Combinatorias , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Masculino , Estructura Molecular , Pirazoles/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Evaluación Preclínica de Medicamentos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Moleculares , Piridinas/síntesis química , Piridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Imidazoles/química , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Biológicos , Piridinas/síntesis química , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Amidas/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.
Asunto(s)
Benzoxazinas/química , Química Farmacéutica/métodos , Oxazinas/síntesis química , Oxazinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Área Bajo la Curva , Benzoxazinas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Isoformas de Proteínas , Relación Estructura-ActividadRESUMEN
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Triazoles/química , Triazoles/farmacología , Animales , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/farmacocinética , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/química , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Piridinas/farmacocinética , Triazoles/farmacocinéticaRESUMEN
Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.
Asunto(s)
Antígenos Dermatofagoides/química , Proteínas de Artrópodos/antagonistas & inhibidores , Proteínas de Artrópodos/química , Asma/tratamiento farmacológico , Cisteína Endopeptidasas/química , Hipersensibilidad/tratamiento farmacológico , Administración Oral , Alérgenos/inmunología , Secuencias de Aminoácidos , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Peso Molecular , Péptidos/química , Unión Proteica , Pyroglyphidae/inmunologíaRESUMEN
A recent metabolic scaling theory predicts that plants minimize resistance to hydraulic conduction in the bulk transport network by narrowing the diameter of xylem conduits distally. We hypothesized that trees growing at high altitude or on nutrient-depleted soils would prioritize survival over minimizing hydraulic resistance, and that their vascular systems would be structured differently from those of trees growing under more benign conditions. In fact, conduits were observed to narrow towards the periphery of vascular system within all 45 trees of three species we investigated, and scaling relationships were indistinguishable across a range of environments. Thus, conduit tapering relationships appear to be invariant with respect to environmental conditions.
Asunto(s)
Altitud , Ecosistema , Suelo , Árboles/anatomía & histología , Xilema/anatomía & histología , Fagaceae/anatomía & histología , Picea/anatomía & histología , Pinus sylvestris/anatomía & histologíaRESUMEN
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
Asunto(s)
Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/farmacología , Carbamatos/química , Carbamatos/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Peso Molecular , Oxazoles/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Sensibilidad y Especificidad , Relación Estructura-ActividadRESUMEN
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/síntesis química , Indoles/farmacología , Transporte Biológico Activo/efectos de los fármacos , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Indoles/química , Leucocitos Mononucleares/efectos de los fármacos , Estructura Molecular , Peso Molecular , Relación Estructura-ActividadRESUMEN
This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.