RESUMO
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Assuntos
Indazóis/química , Oxazóis/química , Inibidores de Fosfoinositídeo-3 Quinase , Doenças Respiratórias/tratamento farmacológico , Sulfonamidas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Feminino , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indóis , Isoenzimas/antagonistas & inibidores , Masculino , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Oxazóis/farmacocinética , Oxazóis/farmacologia , Piperazinas , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Th2/imunologiaRESUMO
Systemic inflammation induces cytokine synthesis within the central nervous system. This results in sickness behaviour and may exacerbate ongoing neuroinflammatory disease. The precise mechanisms underlying the relay of signal from the periphery to the central nervous system are not entirely understood. CD163-positive macrophages occupy a unique position at the blood-brain barrier and upregulate prostaglandin-synthesizing enzymes in response to systemic inflammation. This finding suggests that they might play a role in signalling inflammation to the central nervous system. However, here we demonstrate that de novo brain cytokine transcription during systemic endotoxaemia may be prostaglandin-independent. We therefore set out to interrogate more directly the role of CD163-positive macrophages in immune-to-brain signalling. Intracerebroventricular injections of clodronate liposomes were used to selectively deplete CD163-positive macrophages. We show that de novo brain cytokine synthesis during systemic endotoxaemia persists in the absence of CD163-positive macrophages. Cerebral endothelial cells outnumber CD163-positive macrophages and are arguably better situated to signal circulating inflammatory stimuli to the brain.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Córtex Cerebral/citologia , Citocinas/metabolismo , Regulação da Expressão Gênica/imunologia , Macrófagos/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Ácido Clodrônico/farmacologia , Citocinas/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraventriculares/métodos , Lipossomos/administração & dosagem , Macrófagos/efeitos dos fármacos , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The announcement by Kasahara and Kato of a new redox-cofactor vitamin for mammals, pyrroloquinoline quinone (PQQ), was based on their claim that an enzyme, predicted to be involved in mouse lysine metabolism, is a PQQ-dependent dehydrogenase. However, this claim was dependent on a sequence analysis using databases that inappropriately label beta-propeller sequences as PQQ-binding motifs. What the evidence actually suggests is that the enzyme is an interesting novel protein that has a seven-bladed beta-propeller structure, but there is nothing to indicate that it is a PQQ-dependent dehydrogenase.
