Assuntos
Desenvolvimento Infantil , Diabetes Mellitus Tipo 1/terapia , Saúde da Família , Estilo de Vida Saudável , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Qualidade de Vida , Biomarcadores/sangue , Pré-Escolar , Terapia Combinada/efeitos adversos , Terapia Combinada/tendências , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Sistemas de Infusão de Insulina/efeitos adversos , Agências Internacionais , Corpos Cetônicos/sangue , Pediatria/métodos , Sociedades MédicasRESUMO
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Piridazinas/química , Piridazinas/farmacologia , Piridonas/química , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pironas/síntese química , Pironas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Benzamidas/química , Modelos Animais de Doenças , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Estrutura Molecular , Piridonas , Pironas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologiaRESUMO
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
Assuntos
Anti-Inflamatórios/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridonas/síntese química , Piridonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Diabetes self-management is complex and demanding, and isolation and burnout are common experiences. The Internet provides opportunities for people with diabetes to connect with one another to address these challenges. The aims of this paper are to introduce readers to the platforms on which Diabetes Online Community (DOC) participants interact, to discuss reasons for and risks associated with diabetes-related online activity, and to review research related to the potential impact of DOC participation on diabetes outcomes. METHODS: Research and online content related to diabetes online activity is reviewed, and DOC writing excerpts are used to illustrate key themes. Guidelines for meaningful participation in DOC activities for people with diabetes, families, health care providers, and industry are provided. RESULTS: Common themes around DOC participation include peer support, advocacy, self-expression, seeking and sharing diabetes information, improving approaches to diabetes data management, and humor. Potential risks include access to misinformation and threats to individuals' privacy, though there are limited data on negative outcomes resulting from such activities. Likewise, few data are available regarding the impact of DOC involvement on glycemic outcomes, but initial research suggests a positive impact on emotional experiences, attitudes toward diabetes, and engagement in diabetes management behaviors. CONCLUSION: The range of DOC participants, activities, and platforms is growing rapidly. The Internet provides opportunities to strengthen communication and support among individuals with diabetes, their families, health care providers, the health care industry, policy makers, and the general public. Research is needed to investigate the impact of DOC participation on self-management, quality of life, and glycemic control, and to design and evaluate strategies to maximize its positive impact.