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2.
J Med Chem ; 62(14): 6482-6494, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31265286

RESUMO

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.


Assuntos
Benzotiazóis/farmacologia , Fosfatos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Animais , Benzotiazóis/química , Benzotiazóis/farmacocinética , Benzotiazóis/uso terapêutico , Colite/tratamento farmacológico , Cães , Descoberta de Drogas , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Fosfatos/química , Fosfatos/farmacocinética , Fosfatos/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Suínos , Porco Miniatura
3.
ACS Med Chem Lett ; 9(10): 1039-1044, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30344914

RESUMO

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 µM).

4.
ACS Med Chem Lett ; 8(5): 549-554, 2017 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-28523109

RESUMO

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.

5.
J Med Chem ; 59(10): 4867-80, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27109867

RESUMO

RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.


Assuntos
Aminoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Sulfonas/farmacologia , Aminoquinolinas/sangue , Aminoquinolinas/química , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Relação Estrutura-Atividade , Sulfonas/sangue , Sulfonas/química
7.
Lancet ; 375(9708): 26; author reply 26-7, 2010 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-20109854
8.
Int J Health Serv ; 39(4): 725-47, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19927412

RESUMO

Policymakers have associated the increasing prevalence and incidence of chronic illness with the threat of unsustainable demands for medical services, requiring deployment of effective demand-management strategies. In this article, the authors consider the rise in policy interest in self-management and examine the metaphors, discourse, official statements, policy developments, and goals shaping the field of chronic illness, especially surrounding the promotion and uptake of self-skills training in England's Expert Patients Programme (EPP). They discuss the shift in relationship between individuals and the state since the 1960s and 1970s; the rise in importance of self-management in relation to an aging population; the evidence and rhetoric associated with policy development; and the relationship of self-care to the notion of the "responsible patient," as seen in policy implementation and EPP course promotion. The authors also draw on qualitative research to examine the transmission of ideology and rhetoric in self-skills training. Self-management policies are part of a shift from patient rights to individual responsibilities, a shift that may be less persuasive than its supporters imagine.


Assuntos
Educação de Pacientes como Assunto/métodos , Participação do Paciente , Formulação de Políticas , Autocuidado , Autoeficácia , Doença Crônica/terapia , Inglaterra , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Desenvolvimento de Programas
9.
Bioorg Med Chem Lett ; 19(1): 27-30, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19058966

RESUMO

Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors.


Assuntos
Furanos , Lipase/antagonistas & inibidores , Compostos de Sulfonilureia/síntese química , Animais , Doenças Cardiovasculares/tratamento farmacológico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Endotélio/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Compostos de Sulfonilureia/farmacologia
10.
Sociol Health Illn ; 29(1): 27-45, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17286704

RESUMO

During the last century demographic and epidemiological transitions have had a radical impact upon health and health service provision. A considerable body of research on the sociological aspects of living with chronic illness has accumulated. Debate has focused on how social environments shape disability-related experiences, and the extent to which individual responses define health outcomes. Through the establishment of the Expert Patients Programme (EPP) in 2001, the Department of Health has sought to enhance NHS patients' self-management capacities. This paper discusses three areas relevant to this: the policy formation process leading up to the EPP's present stage of development; the evidence base supporting claims made for its effectiveness; and the significance of psychological concepts such as self-efficacy in approaches to improving public health. The conclusion discusses NHS developments in primary care and public involvement in health and healthcare, and the implications that initiatives such as the EPP carry for the future. It is argued that to facilitate a constructive process of 'care transition' in response to epidemiological and allied change, awareness of cognitive/psychological factors involved in illness behaviours should not draw attention away from the social determinants and contexts of health.


Assuntos
Pessoas com Deficiência , Transição Epidemiológica , Competência Profissional , Autocuidado , Meio Social , Doença Crônica , Cognição , Atenção à Saúde/tendências , Previsões , Humanos , Atenção Primária à Saúde , Saúde Pública , Autoeficácia
11.
Chronic Illn ; 2(4): 249-61, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17212872

RESUMO

OBJECTIVES: In this paper, we seek to clarify what is known about self-care in chronic illness and the impact of lay-led self-management programmes. The main focus of the paper is the specific 'lay-led' interventions developed by Kate Lorig and her collaborators in the USA, and in the context of the English Expert Patients Programme (EPP). METHODS: A systematic search of relevant databases was undertaken. RESULTS: Seventeen articles and two conference papers met the criteria set. These papers documented the use of condition-specific lay-led self-management programmes and generic lay-led self-management programmes. DISCUSSION: Despite the potential benefits of enhanced self-management, the review of the literature presented here suggests several possible problems associated with the presentation and implementation of initiatives such as the EPP programme. These include the possibility that advocates of public service improvements have on occasion been tempted to overstate the evidence for the relative and absolute effectiveness of lay-led self-management programmes. In addition, the varied experiences of those living with a chronic illness warn against promulgating rigid prescriptions about what patients -should think and do. The evidence to date is indicative of short-term benefits being derived from the provision of lay-led self-management programmes.


Assuntos
Doença Crônica/terapia , Autocuidado/normas , Medicina Baseada em Evidências , Humanos
12.
Soc Sci Med ; 59(5): 1071-9, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15186906

RESUMO

Since the late 1990s, the term 'partnership' has increasingly been inserted into the literature and rhetoric of the UK health-care system. In this paper, the assumptions and implications surrounding the usage of the term in relation to doctor-patient interaction are examined in the context of paediatric services. The paper considers recent ideas about partnership in medical encounters, especially those of Charles et al., and the extent to which they are applicable to children. The paper then goes on to develop a framework for understanding patient-partnership issues. It is argued that any investigation of partnership will need to take account of the organisational and legal setting, as well as the beliefs and agendas that all parties bring to the medical encounter. In the context of paediatrics, the perspectives of three actors--the child, parent and health service professional--need to be explored. Our framework allows for different sorts of 'coalition' to develop between these actors as they try to reconcile their perspectives in the clinic and offers a situationally contextualised view of partnership. We also argue that these matters require study outside as well as inside the clinic, through the use of a range of methods, including those that help children at home review their involvement in decision making in the clinic.


Assuntos
Modelos Organizacionais , Relações Pais-Filho , Pediatria/organização & administração , Relações Médico-Paciente , Adulto , Criança , Tomada de Decisões , Pesquisa sobre Serviços de Saúde , Humanos , Programas Nacionais de Saúde/organização & administração , Reino Unido
13.
Soc Sci Med ; 55(9): 1619-33, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12297247

RESUMO

This study is concerned with how young people with moderate to severe asthma live with and explain the disorder and manage the resulting symptoms. Based on in-depth interviews with 55 young people aged 11-16 living in West London, it shows that asthma restricted their lives at school and recreationally but that they were actively involved with their condition and its management. The study reveals that while prescribed medicines in the form of inhalers were used as the primary means of coping with asthma episodes, the young people were concerned about being dependent on such medicines, in line with more general ambivalence in late modern cultures about the long term use of prescribed medicines. It also demonstrates how social relations in particular contexts help to determine the extent to which asthma episodes can be managed.


Assuntos
Adaptação Psicológica , Asma/psicologia , Psicologia do Adolescente , Perfil de Impacto da Doença , Adolescente , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Asma/prevenção & controle , Criança , Cuidado Periódico , Feminino , Humanos , Estilo de Vida , Londres , Masculino , Nebulizadores e Vaporizadores , Qualidade de Vida , Recreação , Serviços de Saúde Escolar , Esportes
14.
J Adv Nurs ; 39(5): 432-40, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12175352

RESUMO

AIM: This aim of this paper is to examine critically the implications for women of a gendered construction of coronary heart disease. DESIGN: The paper takes the form of a literature review between 1969 and 2002 of nursing, medical and social science literature written in the English language that explores the experience of women with coronary heart disease. FINDINGS: Coronary heart disease has been constructed during the 20th century as a disease of affluence that affects high achieving men. However coronary heart disease is a major cause of morbidity and mortality among women. The literature suggests that this gendered construction has influenced not only health professionals' perceptions of coronary heart disease but also lay theories of candidature, so that the collective consciousness sees women as being at low risk. Moreover, that this construction of coronary heart disease as a male disease has led to a service provision engineered to meet male needs that arguably can be seen to militate against women. This has resulted in women being diagnosed when they are further along the disease trajectory. It also means that once diagnosis has made then they are less likely to be referred for investigations, treatment and rehabilitation. CONCLUSION: The implications of this construction for the care of women with coronary heart disease may result in 'gender-neutral' care. This may mean that decisions about care are made in the light of nurses' own knowledge and experience of nursing male patients, with the consequence that women patients' individual needs are not met.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Surtos de Doenças , Procedimentos Cirúrgicos Cardíacos/mortalidade , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/terapia , Feminino , Humanos , Infarto do Miocárdio/etiologia , Cuidados de Enfermagem/métodos , Fatores de Risco , Fatores Sexuais
16.
In. Nordenfelt, Lennart. Concepts and measurement of quality of life in health care. Dordrecht, Kluwer Academic, 1994. p.117-134.
Monografia em Inglês | CidSaúde - Cidades saudáveis | ID: cid-15621
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