RESUMEN
Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.
Asunto(s)
Compuestos Aza/farmacología , Indazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Compuestos Aza/síntesis química , Compuestos Aza/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Indazoles/síntesis química , Indazoles/química , Estructura Molecular , Receptores CCR1/metabolismo , Relación Estructura-ActividadRESUMEN
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirazoles/química , Receptores CCR1/metabolismo , Relación Estructura-ActividadRESUMEN
Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1-/- animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1-/- mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain.
Asunto(s)
Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Dolor/inmunología , Receptores CCR1/inmunología , Ácido Acético , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea/métodos , Movimiento Celular/genética , Movimiento Celular/inmunología , Citometría de Flujo , Adyuvante de Freund , Hiperalgesia/inducido químicamente , Hiperalgesia/genética , Hiperalgesia/inmunología , Leucocitos/inmunología , Leucocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/inmunología , Células Mieloides/metabolismo , Infiltración Neutrófila/genética , Neutrófilos/metabolismo , Dolor/inducido químicamente , Dolor/genética , Dimensión del Dolor/métodos , Peritonitis/genética , Peritonitis/inmunología , Peritonitis/metabolismo , Receptores CCR1/antagonistas & inhibidores , Receptores CCR1/genéticaRESUMEN
BACKGROUND: Turnover of licensed nursing staff in long-term care (LTC) settings (e.g., nursing homes) is a mounting concern and is associated with poor quality of care and low staff morale. Retention and turnover research in LTC have focused primarily on direct care workers (i.e., nurse aides) leaving the issues largely unexplored for licensed nursing staff (i.e., registered nurses and licensed practical nurses). OBJECTIVE: The main objective of this study was to understand factors that influence nurses' intentions to remain employed at their current job. DESIGN: Qualitative descriptive study. SETTINGS: Seven nursing homes in Ontario, Canada. PARTICIPANTS: A convenience sample of forty-one licensed LTC nurses. METHODS: Data were collected through focus groups conducted at each of the participating nursing homes. Focus group discussions were transcribed verbatim. Directed content analysis was used to identify and develop themes. RESULTS: Work conditions were a salient element affecting nurses' intention to stay and included impact of regulations on nurse role flexibility and professional judgment, an underfunded system contributing to insufficient resources and staffing, and a lack of supportive leadership. Factors promoting nurses' willingness to stay included the development of meaningful relationships with residents and staff and opportunities for learning and professional development. Nurses also considered personal and life circumstances (e.g., marital status and seniority) when discussing intention to stay. CONCLUSIONS: Nurses in this study weighed positive and negative work-related factors as well as personal circumstances to determine their intent to stay. Developing a more individualized approach to address attrition of licensed nurses in LTC may be the most successful strategy for improving retention of highly skilled staff in this sector.
Asunto(s)
Empleo , Casas de Salud/organización & administración , Personal de Enfermería , Adulto , Anciano , Femenino , Humanos , Concesión de Licencias , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , OntarioRESUMEN
Sphingosine-1-phosphate (S1P) receptors are critical for lymphocyte egress from secondary lymphoid organs, and S1P receptor modulators suppress lymphocyte circulation. However, the role of S1P receptors on monocytes is less clear. To elucidate this, we systematically evaluated monocytes in rats and mice, both in naive and inflammatory conditions, with S1P receptor modulators FTY720 and BAF312. We demonstrate that S1P receptor modulators reduce circulating monocytes in a similar time course as lymphocytes. Furthermore, total monocyte numbers were increased in the spleen and bone marrow, suggesting that S1P receptor modulation restricts egress from hematopoietic organs. Monocytes treated ex vivo with FTY720 had reduced CD40 expression and TNF-α production, suggesting a direct effect on monocyte activation. Similar reductions in protein expression and cytokine production were also found in vivo. Suppression of experimental autoimmune encephalomyelitis in mice and rats by FTY720 correlated with reduced numbers of lymphocytes and monocytes. These effects on monocytes were independent of S1P3, as treatment with BAF312, a S1P1,4,5 modulator, led to similar results. These data reveal a novel role for S1P receptors on monocytes and offer additional insights on the mechanism of action of S1P receptor modulators in disease.
Asunto(s)
Monocitos/efectos de los fármacos , Monocitos/metabolismo , Glicoles de Propileno/farmacología , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/análogos & derivados , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Movimiento Celular/inmunología , Citocinas/biosíntesis , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Clorhidrato de Fingolimod , Células Asesinas Naturales/metabolismo , Recuento de Leucocitos , Ratones , Monocitos/inmunología , Neutrófilos/metabolismo , Ratas , Esfingosina/farmacología , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
BACKGROUND: Care providers' interactions with residents are an important element in long-term care settings. This study aimed at examining the association between care providers' relational behaviors and affect and mood of residents with dementia over different caregiving situations and with different residents. METHODS: This study utilized a repeated-measures design. Thirty-eight residents with a diagnosis of dementia and 35 care providers from three nursing homes in Ontario, Canada, participated in the study. Care providers' relational behaviors and residents' mood and affect were assessed using direct observation methods and self-rating scales. RESULTS: The care providers' relational behavior varied according to the caregiving situation, with the most effective relational behaviors observed during interpersonal interactions and the least effective during mealtimes. Less effective relational behaviors were observed between care providers and residents that were perceived as more resistive to care. In addition, effective relational behaviors were associated with positive mood and affect of the residents. CONCLUSION: These findings emphasize the importance of acknowledging and enhancing care providers' relational behaviors when caring for persons with dementia living in long-term care settings.
Asunto(s)
Afecto , Cuidadores/psicología , Demencia/enfermería , Relaciones Interpersonales , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Casas de Salud , Ontario , Pacientes/psicología , Recursos HumanosRESUMEN
Multiple sclerosis (MS) is a devastating autoimmune disease that affects more than 1 million people worldwide and severely compromises motor and sensory function through demyelination and axonal loss. This review covers current therapies, lessons learned from failed clinical trials, genetic susceptibility, key cell types involved, animal models, gene expression, and biomarker information. The current first-line therapies for MS include the type I interferons (IFN-I) and glatiramer acetate (GA) but because of their limited effectiveness new therapeutic modalities are required. Tysabri is an anti very late antigen-4 antibody that antagonizes the migration of multiple cell types and appears more efficacious as compared to the IFNs or GA. Tysabri blocks the transmigration of T cells and monocytes, which indicates that blocking multiple cell types may increase the effectiveness of the therapy. However, this therapy may increase the risk of progressive multifocal leukoencephalopathy. The major cell types hypothesized to be pathogenic include T cells and antigen-presenting cells, including B cells. The correlation of the animal model experimental autoimmune encephalomyelitis (EAE) of MS and its predictive value to determine efficacy in the clinic appears limited. However, all current therapies do demonstrate efficacy in EAE models. There are also examples of mechanisms that have worked in EAE but have failed in the clinic, such as the TNFα antagonists and anti-p40 (a subunit of IL-12 and IL-23). The MS field would benefit if clinical biomarkers were available to monitor clinical efficacy. The etiology of MS remains elusive but additional understanding of mechanisms involved in the pathogenesis of MS may guide us to more effective treatment and management of this autoimmune disease.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/terapia , Predisposición Genética a la Enfermedad , Humanos , Inmunosupresores/farmacología , Inmunoterapia/métodos , Esclerosis Múltiple/genéticaRESUMEN
T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-theta was sequestered away from the Treg immunological synapse. Furthermore, PKC-theta blockade enhanced Treg function, demonstrating PKC-theta inhibits Treg-mediated suppression. Inhibition of PKC-theta protected Treg from inactivation by TNF-alpha, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.
Asunto(s)
Sinapsis Inmunológicas/inmunología , Inflamación/inmunología , Isoenzimas/metabolismo , Proteína Quinasa C/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Anciano , Animales , Artritis Reumatoide/inmunología , Colitis/inmunología , Colitis/prevención & control , Inhibidores Enzimáticos/farmacología , Retroalimentación Fisiológica , Humanos , Interferón gamma/metabolismo , Isoenzimas/antagonistas & inhibidores , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteína Quinasa C/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
The provision of care for frail older adults in Long-term care settings is challenging. It requires not only specialized knowledge and skills, but also supportive commitment on the part of directors of care to their nurse supervisors (registered nurses and registered practical nurses) and unregulated healthcare staff. In these complex work environments, communication and leadership are critical to staff job satisfaction. Therefore, it is essential that directors of care represent a source of support for their nurse supervisors. The purpose of this multi-site study was to examine the relationships among perceived support from directors of care, and nurse supervisors' job stress and job satisfaction. Forty-five per cent of the total variance in job satisfaction of nurse supervisors was explained by supervisory support, stress and job category (registered nurse vs. registered practical nurse). Greater supervisory support was also associated with reduced job stress. These findings are essential in developing strategies to improve the nurse supervisory role in long-term care settings.
Asunto(s)
Actitud del Personal de Salud , Agotamiento Profesional/prevención & control , Satisfacción en el Trabajo , Enfermeras Administradoras , Supervisión de Enfermería/organización & administración , Apoyo Social , Adulto , Análisis de Varianza , Agotamiento Profesional/etiología , Agotamiento Profesional/psicología , Estudios Transversales , Femenino , Humanos , Relaciones Interprofesionales , Liderazgo , Cuidados a Largo Plazo/organización & administración , Cuidados a Largo Plazo/psicología , Masculino , Modelos Psicológicos , Enfermeras Administradoras/organización & administración , Enfermeras Administradoras/psicología , Rol de la Enfermera/psicología , Casas de Salud/organización & administración , Investigación Metodológica en Enfermería , Salud Laboral , Ontario , Cultura Organizacional , Factores de Riesgo , Lugar de Trabajo/organización & administración , Lugar de Trabajo/psicologíaRESUMEN
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Química Farmacéutica/métodos , Nitrilos/química , Dominio Catalítico , Dipéptidos/química , Diseño de Fármacos , Humanos , Modelos Químicos , Conformación Molecular , Nitrilos/clasificación , Péptidos/química , Piperidinas/química , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteína Quinasa C-theta , Relación Estructura-ActividadRESUMEN
Protein kinase C theta (PKCtheta) is essential for T cell activation, as it is required for the activation of NF-kappaB and expression of IL-2. PKCtheta has also been shown to affect NFAT activation and Th2 differentiation. To better understand the role of PKCtheta in the regulation of T helper cells, we used PKCtheta-deficient DO11.10 transgenic T cells to study its role in vitro. DO11.10 Th1 cells deficient in PKCtheta produced significantly less TNF-alpha and IL-2. The expression of Th2 cytokines, including IL-4, IL-5, IL-10, IL-13 and IL-24 was significantly reduced in PKCtheta-deficient T cells. Moreover, the expression of the Th2 transcription factor, GATA3, was significantly reduced in PKCtheta-deficient T cells. Overexpression of GATA3 by retroviral infection in PKCtheta-deficient T cells resulted in increased expansion of IL-4-producing T cells and higher IL-4 production than that of wild type Th2 cells. IL-5, IL-10, IL-13 and IL-24 expressions were also rescued by GATA3 overexpression. Our observations suggest that PKCtheta regulates Th2 cytokine expression via GATA3.
Asunto(s)
Citocinas/biosíntesis , Factor de Transcripción GATA3/fisiología , Isoenzimas/fisiología , Proteína Quinasa C/fisiología , Células Th2/enzimología , Animales , Células Cultivadas , Citocinas/genética , Factor de Transcripción GATA3/biosíntesis , Factor de Transcripción GATA3/genética , Interferón gamma/biosíntesis , Interferón gamma/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Proteína Quinasa C-theta , Células Th2/inmunología , Células Th2/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Cathepsin S is a major histocompatibility complex (MHC) class II associated invariant chain (Ii) degrading enzyme expressed in antigen presenting cells such as B cells and dendritic cells. This enzyme is essential for MHC class II associated antigen processing and presentation to CD4(+) T cells. Compound I, a selective, reversible and orally bioavailable, inhibitor of cathepsin S, with molecular IC(50)=9 nM, has been recently described. We have tested the effects of compound I in a trans vivo model of delayed-type hypersensitivity. Human peripheral blood mononuclear cells (7-10 x 10(6)) from tetanus-sensitized donors were co-injected with tetanus toxoid (0.25 Lf) into C57Bl/6 mouse footpads. At 24 h, significant footpad swelling (+0.024+/-0.001 cm) characterized by an influx of mouse neutrophils and monocytes was observed. Injection of peripheral blood mononuclear cells alone caused negligible swelling (0.002+/-0.0002 cm). Anti-human MHC class II (HLA-DR, DP, DQ) antibody (5 mg/kg, i.p.) inhibited the swelling 91+/-7%, thus demonstrating a role of human antigen presenting cells in this model. Compound I (10, 30, and 100 mg/kg, p.o.) inhibited the response with an ED50 of approximately 18 mg/kg. Compound III, a less active analogue (molecular IC50>20 microM) had no effect. Furthermore, pretreatment of peripheral blood mononuclear cells with 10 nM compound II, an irreversible inhibitor (molecular IC50=11 nM) inhibited swelling 87+/-4%. These findings support the role of cathepsin S in human delayed-type hypersensitivity. Inhibition of cathepsin S with compound I may be useful in the treatment of human autoimmune diseases like rheumatoid arthritis and multiple sclerosis.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hipersensibilidad Tardía/prevención & control , Administración Oral , Animales , Disponibilidad Biológica , Catepsinas/genética , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Hipersensibilidad Tardía/inmunología , Hipersensibilidad Tardía/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The practices of managers and registered nurses (RNs) in long-term care facilities are frequently ineffective in assisting the licensed practical nurses (LPNs) and healthcare aides (HCAs) whom they supervise. Little research exists that examines the area of supportive relationships between nursing staff and supervisors in these settings. The purpose of this study was to gather data that could improve management practices in long-term care residential facilities and enhance the quality of the supervisory relationships between supervisors (nurse managers and RNs) and care providers (HCAs and LPNs) in these settings. The study also identified factors that influence the supervisors' ability to establish supportive relationships with care providers. The challenges and barriers to nurse managers and leaders related to enacting supportive behaviors are discussed as well as their implications for long-term care settings.
Asunto(s)
Casas de Salud/organización & administración , Personal de Enfermería/organización & administración , Supervisión de Enfermería/normas , Administración de Personal , Apoyo Social , Adulto , Comunicación , Femenino , Grupos Focales , Conducta de Ayuda , Humanos , Liderazgo , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Rol de la Enfermera , Asistentes de Enfermería/psicología , Personal de Enfermería/psicología , Enfermería Práctica , Ontario , Recompensa , ConfianzaRESUMEN
The design and synthesis of dipeptidyl disulfides and dipeptidyl benzoylhydrazones as selective inhibitors of the cysteine protease Cathepsin S are described. These inhibitors were expected to form a slowly reversible covalent adduct of the active site cysteine of Cathepsin S. Formation of the initial adduct was confirmed by mass spectral analysis. The nature and mechanism of these adducts was explored. Kinetic analysis of the benzoyl hydrazones indicate that these inhibitors are acting as irreversible inhibitors of Cathepsin S. Additionally, the benzoylhydrazones were shown to be potent inhibitors of Cathepsin S processing of Class II associated invariant peptide both in vitro and in vivo.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Disulfuros/síntesis química , Disulfuros/farmacología , Hidrazonas/síntesis química , Hidrazonas/farmacología , Animales , Catepsina B/antagonistas & inhibidores , Línea Celular , Diseño de Fármacos , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Elastasa Pancreática/antagonistas & inhibidores , Pruebas de Precipitina , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.