RESUMO
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.
RESUMO
Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.
Assuntos
Benzoxazinas/síntese química , Benzoxazinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Pirazóis/síntese química , Pirazóis/farmacologia , Administração Oral , Animais , Benzoxazinas/química , Técnicas de Química Combinatória , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Masculino , Estrutura Molecular , Pirazóis/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Modelos Moleculares , Piridinas/síntese química , Piridinas/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Imidazóis/química , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Modelos Biológicos , Piridinas/síntese química , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzoxazinas/química , Química Farmacêutica/métodos , Oxazinas/síntese química , Oxazinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Área Sob a Curva , Benzoxazinas/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Inflamação , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Isoformas de Proteínas , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/farmacocinética , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/química , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Piridinas/farmacocinética , Triazóis/farmacocinéticaRESUMO
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.
Assuntos
Antígenos de Dermatophagoides/química , Proteínas de Artrópodes/antagonistas & inibidores , Proteínas de Artrópodes/química , Asma/tratamento farmacológico , Cisteína Endopeptidases/química , Hipersensibilidade/tratamento farmacológico , Administração Oral , Alérgenos/imunologia , Motivos de Aminoácidos , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Peso Molecular , Peptídeos/química , Ligação Proteica , Pyroglyphidae/imunologiaRESUMO
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.
Assuntos
Altitude , Ecossistema , Solo , Árvores/anatomia & histologia , Xilema/anatomia & histologia , Fagaceae/anatomia & histologia , Picea/anatomia & histologia , Pinus sylvestris/anatomia & histologiaRESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Oxazóis/farmacologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Indóis/química , Leucócitos Mononucleares/efeitos dos fármacos , Estrutura Molecular , Peso Molecular , Relação Estrutura-AtividadeRESUMO
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.