RESUMEN
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].
RESUMEN
Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
RESUMEN
A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.
Asunto(s)
Descubrimiento de Drogas , Pirimidinas/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirimidinas/administración & dosificación , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazolo[1,5-a]pyrimidin-7-ol 1, resulting in the discovery of CXCR2 receptor antagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 14. The SAR was investigated by systematic variation of the pendant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyrimidine core with a triazolo alternative led to a dual series of antagonists with favourable biological and pharmacokinetic properties.
Asunto(s)
Descubrimiento de Drogas , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
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Indolizinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Células CHO , Cricetinae , Cricetulus , Dermatitis por Contacto/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Semivida , Humanos , Hipersensibilidad/tratamiento farmacológico , Indolizinas/farmacocinética , Indolizinas/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Relación Estructura-Actividad , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4(+) T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3(+) regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3(+) and IL-10(+) CD4(+) T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3(+) and IL-10(+) T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3(+) Treg cells over their Foxp3(-) T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3(+) expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4(+) Foxp3(+) T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10(+) and Foxp3(+) Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.
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Asma/inmunología , Calcitriol/farmacología , Factores de Transcripción Forkhead/metabolismo , Interleucina-10/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Animales , Asma/tratamiento farmacológico , Antígenos CD4/metabolismo , Células Cultivadas , Niño , Citocinas/inmunología , Factores de Transcripción Forkhead/genética , Humanos , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
A library of chemokine antagonists has been synthesized using a combination of solid and solution-phase chemistry. Structures of known chemokine antagonists were used to produce a pharmacophore which served to guide monomer selection. Several combinations of monomers have resulted in providing novel chemokine antagonists which in some cases display dual chemokine receptor antagonism.
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Quimiocinas/antagonistas & inhibidores , Diseño de Fármacos , Bibliotecas de Moléculas Pequeñas , Animales , Línea Celular , Cricetinae , CricetulusRESUMEN
The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.
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Agonistas del Receptor de Adenosina A2 , Compuestos Aza/síntesis química , Ácidos Carboxílicos/síntesis química , Nucleósidos/síntesis química , Nucleótidos de Pirimidina/síntesis química , Animales , Compuestos Aza/metabolismo , Compuestos Aza/farmacología , Células CHO , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacología , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos/métodos , Humanos , Nucleósidos/metabolismo , Nucleósidos/farmacología , Nucleótidos de Pirimidina/metabolismo , Nucleótidos de Pirimidina/farmacología , Ratas , Receptor de Adenosina A2A/metabolismoRESUMEN
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.
Asunto(s)
Acetatos/química , Antiinflamatorios/química , Piridinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/síntesis química , Acetatos/farmacocinética , Administración Oral , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Humanos , Microsomas Hepáticos/metabolismo , Permeabilidad , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
Signaling through the TLR family of molecular pattern recognition receptors has been implicated in the induction of innate and adaptive immune responses. A role for TLR signaling in the maintenance and/or regulation of Treg function has been proposed, however its functional relevance remains unclear. Here we have shown that TLR9 is highly expressed by human Treg secreting the antiinflammatory cytokine IL-10 induced following stimulation of blood and tissue CD3+ T cells in the presence of 1alpha,25-dihydroxyvitamin D3 (1alpha25VitD3), the active form of Vitamin D, with or without the glucocorticoid dexamethasone. By contrast, TLR9 was not highly expressed by naturally occurring CD4+CD25+ Treg or by Th1 and Th2 effector cells. Induction of TLR9, but not other TLRs, was IL-10 dependent and primarily regulated by 1alpha25VitD3 in vitro. Furthermore, ingestion of calcitriol (1alpha25VitD3) by human volunteers led to an increase of both IL-10 and TLR9 expression by CD3+CD4+ T cells analyzed directly ex vivo. Stimulation of 1alpha25VitD3-induced IL-10-secreting Treg with TLR9 agonists, CpG oligonucleotides, resulted in decreased IL-10 and IFN-gamma synthesis and a concurrent loss of regulatory function, but, unexpectedly, increased IL-4 synthesis. We therefore suggest that TLR9 could be used to monitor and potentially modulate the function of 1alpha25VitD3-induced IL-10-secreting Treg in vivo, and that this has implications in cancer therapy and vaccine design.
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Calcitriol/farmacología , Interleucina-10/biosíntesis , Linfocitos T Reguladores/fisiología , Receptor Toll-Like 9/fisiología , Adulto , Anciano , Dexametasona/farmacología , Humanos , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos/farmacología , ARN Mensajero/análisis , Receptores de Calcitriol/fisiología , Linfocitos T Reguladores/efectos de los fármacos , Receptor Toll-Like 9/genéticaRESUMEN
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
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Acetatos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/química , Animales , Disponibilidad Biológica , Eosinófilos/efectos de los fármacos , Humanos , Ratas , Relación Estructura-ActividadRESUMEN
Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.
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Asma , Receptores de Quimiocina , Animales , Asma/tratamiento farmacológico , Quimiocina CCL11 , Quimiocinas/antagonistas & inhibidores , Eosinófilos , Humanos , Hipersensibilidad/tratamiento farmacológico , Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Citocinas/uso terapéuticoRESUMEN
Macrophage-derived chemokine [CC chemokine ligand 22 (CCL22)] and thymus- and activation-regulated chemokine (CCL17) mediate cellular effects, principally by binding to their receptor CC chemokine receptor 4 (CCR4) and together, constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles within the body. This study demonstrates that CCL22 and CCL17 stimulate pertussis toxin-sensitive elevation of intracellular calcium in the CEM leukemic T cell line and human peripheral blood-derived T helper type 2 (Th2) cells. Inhibition of phospholipase C (PLC) resulted in the abrogation of chemokine-mediated calcium mobilization. Chemokine-stimulated calcium responses were also abrogated completely by the inhibition of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor-mediated calcium release. Chemotactic responses of CEM and human Th2 cells to CCL17 and CCL22 were similarly abrogated by inhibition of PLC and inhibition of novel, Ca2+-independent/diacylglycerol-dependent protein kinase C (PKC) isoforms. Inhibition of Ins(1,4,5)P3 receptor-mediated calcium release from intracellular stores had no effect on chemotactic responses to CCR4 ligands. Taken together, this study provides compelling evidence of an important role for PLC and diacylglycerol-dependent effector mechanisms (most likely involving novel PKC isoforms) in CCL17- and CCL22-stimulated, directional cell migration. In this regard, CCL22 stimulates phosphatidylinositol-3 kinase-independent phosphorylation of the novel delta isoform of PKC at threonine 505, situated within its activation loop--an event closely associated with increased catalytic activity.
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Quimiocinas CC/fisiología , Quimiotaxis/fisiología , Fosfatidilinositol Diacilglicerol-Liasa/fisiología , Procesamiento Proteico-Postraduccional/fisiología , Receptores de Quimiocina/fisiología , Linfocitos T/efectos de los fármacos , Acetofenonas/farmacología , Benzopiranos/farmacología , Calcio/fisiología , Canales de Calcio/fisiología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Dominio Catalítico , Línea Celular Tumoral/citología , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/fisiología , Quimiocina CCL17 , Quimiocina CCL22 , Quimiocinas CC/genética , Quimiotaxis/efectos de los fármacos , Cromonas/farmacología , Diglicéridos/fisiología , Estrenos/farmacología , Humanos , Indoles/farmacología , Inositol 1,4,5-Trifosfato/fisiología , Receptores de Inositol 1,4,5-Trifosfato , Leucemia-Linfoma de Células T del Adulto/patología , Morfolinas/farmacología , Toxina del Pertussis/farmacología , Fosfatidilinositol 3-Quinasas/fisiología , Fosfatidilinositol Diacilglicerol-Liasa/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Fosfotreonina/química , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirroles/farmacología , Pirrolidinonas/farmacología , Receptores CCR4 , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/fisiología , Proteínas Recombinantes de Fusión/farmacología , Linfocitos T/citología , Células Th2/citología , Células Th2/efectos de los fármacosRESUMEN
Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7-8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity.
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Enfermedades del Sistema Inmune/inmunología , Linfocitos T Reguladores/inmunología , Autoinmunidad , Humanos , Enfermedades del Sistema Inmune/terapia , Tolerancia Inmunológica , Inmunoterapia/métodos , Infecciones/inmunología , Neoplasias/inmunologíaRESUMEN
Repetitive, acute inflammatory insults elicited by cigarette smoke (CS) contribute to the development of chronic obstructive pulmonary disease (COPD), a disorder associated with lung inflammation and mucus hypersecretion. Presently, there is a poor understanding of the acute inflammatory mechanisms involved in this process. The aims of this study were to develop an acute model to investigate temporal inflammatory changes occurring after CS exposure. Rats were exposed to whole body CS (once daily) generated from filtered research cigarettes. Initial studies indicated the generation of a neutrophilic/mucus hypersecreting lung phenotype in <4 days. Subsequent studies demonstrated that just two exposures to CS (15 h apart) elicited a robust inflammatory/mucus hypersecretory phenotype that was used to investigate mechanisms driving this response. Cytokine-induced neutrophil chemoattractants (CINCs) 1-3, the rat growth-related oncogene-alpha family homologs, and IL-1beta demonstrated time-dependent increases in lung tissue or lavage fluid over the 24-h period following CS exposure. The temporal changes in the neutrophil chemokines, CINCs 1-3, mirrored increases in neutrophil infiltration, indicative of a role in neutrophil migration. In addition, a specific CXCR2 antagonist, SB-332235, effectively inhibited CS-induced neutrophilia in a dose-dependent manner, supporting this conclusion. This modeling of the response of the rat airways to acute CS exposure indicates 1) as few as two exposures to CS will induce a phenotype with similarities to COPD and 2) a novel role for CINCs in the generation of this response. These observations represent a paradigm for the study of acute, repetitive lung insults that contribute to the development of chronic disease.
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Pulmón/metabolismo , Moco/metabolismo , Nicotiana/efectos adversos , Neumonía/etiología , Receptores de Interleucina-8B/metabolismo , Humo/efectos adversos , Animales , Ligandos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its cellular effects principally by binding to its receptor CCR4, and together they constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles in the body. We report the CCL22-induced accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P(3)) in the leukemic T cell line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM cells in a pertussis toxin-sensitive manner. Although the PI(3,4,5)P(3) accumulation along with the pertussis toxin-susceptible phosphorylation of protein kinase B were sensitive to the two phosphoinositide 3-kinase inhibitors, LY294002 and wortmannin, cell migration was unaffected. However, cell migration was abrogated with the Rho-dependent kinase inhibitor, Y-27632. These data demonstrate that although there is PI(3,4,5)P(3) accumulation downstream of CCR4, phosphoinositide 3-kinase activity is a dispensable signal for CCR4-stimulated chemotaxis of Th2 cells and the CEM T cell line.