RESUMEN
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18/CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32. Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45, which demonstrated a favorable in vitro PK profile, although they displayed species disconnects in the in vivo PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.
Asunto(s)
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/química , Diseño de Fármacos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To explore children's' and families' experiences of using intensive care diaries after discharge and the role of diaries in the process of recovering from a stay in the paediatric intensive care unit. DESIGN AND SETTING: Qualitative, exploratory design. Data collection consisted of semi-structured interviews with five children and their families, conducted four to six months after discharge from the intensive care unit. Inclusion criteria were children and their families, with a stay for more than three days who had a diary written for them. Data were analysed using thematic analysis FINDINGS: Three main themes emerged: (i) value to the entire family, (ii) creating memories, (iii) the importance of pictures. CONCLUSION: Diaries were used after discharge as a support for both children and families and played a role in making the paediatric intensive care experience meaningful by providing explanations and coherence. The findings suggest that a diary can serve as a catalyst for the coping process of the family unit. Findings also confirm how the children's memories are characterised by a sense of unreality. The diary could thus help fill in some of the missing picture to support the children in understanding their story.
Asunto(s)
Familia/psicología , Registros Médicos/normas , Escritura/normas , Adaptación Psicológica , Adulto , Niño , Femenino , Humanos , Unidades de Cuidado Intensivo Pediátrico/organización & administración , Masculino , Investigación CualitativaRESUMEN
Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.
Asunto(s)
Aminopiridinas/farmacología , Diseño de Fármacos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Aminopiridinas/síntesis química , Aminopiridinas/química , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Células de Riñón Canino Madin Darby/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure-activity studies starting from 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063, 4) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/síntesis química , Receptor de Adenosina A2A/química , Tiazoles/síntesis química , para-Aminobenzoatos/síntesis química , Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/metabolismo , Sitios de Unión , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Receptor de Adenosina A2A/metabolismo , Solubilidad , Relación Estructura-Actividad , Tiazoles/química , Agua/química , para-Aminobenzoatos/químicaRESUMEN
We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
Asunto(s)
Antipsicóticos/química , Ligandos , Quinolonas/química , Receptor Muscarínico M1/agonistas , Receptores de Dopamina D2/agonistas , Antipsicóticos/síntesis química , Antipsicóticos/farmacocinética , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Quinolonas/síntesis química , Quinolonas/farmacocinética , Receptor Muscarínico M1/metabolismo , Receptores de Dopamina D2/metabolismo , Relación Estructura-ActividadRESUMEN
A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.
Asunto(s)
Diseño de Fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Regulación Alostérica , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Unión Proteica/efectos de los fármacos , Receptor del Glutamato Metabotropico 5 , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
AIM: This paper reports a concept analysis of family-centred nursing care of hospitalized children. BACKGROUND: Family-centred care describes a practice aimed towards involving the family in all aspects of care. Previous analyses explore the colloquial use of the concept. An increasing amount of scientific papers apply the concept with seemingly little consistency in use. DATA SOURCES: A systematic literature search including articles from 1951 to 2009 resulted in a sample of 25 research articles. REVIEW METHODS: A theoretical concept analysis influenced by Risjord's distinction between theoretical and colloquial analyses and based on the principles developed by Morse, Hupcey and Penrod was used to examine the structure and scientific maturity of the concept. FINDINGS: There is good agreement on the defining attributes of the concept, but they are described by sub concepts in need of clarification. The relationship between family and professionals is characterized by a mutual dependency and shared responsibility for the child's care, which may have both positive and negative consequences and holds potential areas of conflict not fully explained by the attribute of partnership. The nature of partnership remains unclear and it may therefore not yet be a relevant attribute. The concept is defined from the perspective of professionals and families, mostly represented by mothers. Few attempts have been made to operationalize the concept. CONCLUSION: Family-centred care is a partially mature and highly abstract concept. Developing a theory of family-centred care could position the concept in a theoretical context and should also include the perspective of the sick child.
Asunto(s)
Enfermería de la Familia , Modelos de Enfermería , Teoría de Enfermería , Enfermería Pediátrica/métodos , Relaciones Profesional-Familia , Rol , Niño , Niño Hospitalizado , Preescolar , Competencia Clínica , Bases de Datos Bibliográficas , Humanos , Lactante , Recién Nacido , Padres/psicología , Enfermería Pediátrica/organización & administración , Terminología como AsuntoRESUMEN
The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/síntesis química , Antiparkinsonianos/síntesis química , Organofosfatos/síntesis química , Profármacos/síntesis química , Tiazoles/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Células CHO , Células CACO-2 , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , Cristalografía por Rayos X , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Modelos Moleculares , Organofosfatos/farmacocinética , Organofosfatos/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , AguaRESUMEN
The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
Asunto(s)
Bencenoacetamidas/síntesis química , Benzoxazinas/síntesis química , Nootrópicos/síntesis química , Oxazinas/síntesis química , Piperidinas/síntesis química , Receptor Muscarínico M1/agonistas , Regulación Alostérica , Animales , Bencenoacetamidas/farmacocinética , Bencenoacetamidas/farmacología , Benzoxazinas/farmacocinética , Benzoxazinas/farmacología , Encéfalo/metabolismo , Calcio/metabolismo , Línea Celular , Cricetinae , Cricetulus , Femenino , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Oxazinas/farmacocinética , Oxazinas/farmacología , Piperidinas/farmacocinética , Piperidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Herein we describe the discovery of a series of novel adenosine A(2A) receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson's Disease.
Asunto(s)
Amidas/farmacología , Ácidos Carboxílicos/farmacología , Antagonistas de Receptores Purinérgicos P1/farmacología , Receptor de Adenosina A2A/efectos de los fármacos , Amidas/química , Ácidos Carboxílicos/química , Antagonistas de Receptores Purinérgicos P1/química , Relación Estructura-ActividadRESUMEN
Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (38) is a potent GlyT-1 inhibitor (IC50=59 nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.
Asunto(s)
Aminoácidos/síntesis química , Aminoácidos/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Aminoácidos/química , Aminoácidos/farmacocinética , Barrera Hematoencefálica , Células CACO-2 , Humanos , Relación Estructura-ActividadRESUMEN
Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC(50)=150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c.