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1.
PLoS One ; 9(11): e113215, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25405900

RESUMO

RGS18 is a myeloerythroid lineage-specific regulator of G-protein signaling, highly expressed in megakaryocytes (MKs) and platelets. In the present study, we describe the first generation of a RGS18 knockout mouse model (RGS18-/-). Interesting phenotypic differences between RGS18-/- and wild-type (WT) mice were identified, and show that RGS18 plays a significant role in both platelet generation and function. RGS18 deficiency produced a gain of function phenotype in platelets. In resting platelets, the level of CD62P expression was increased in RGS18-/- mice. This increase correlated with a higher level of plasmatic serotonin concentration. RGS18-/- platelets displayed a higher sensitivity to activation in vitro. RGS18 deficiency markedly increased thrombus formation in vivo. In addition, RGS18-/- mice presented a mild thrombocytopenia, accompanied with a marked deficit in MK number in the bone marrow. Analysis of MK maturation in vitro and in vivo revealed a defective megakaryopoiesis in RGS18-/- mice, with a lower bone marrow content of only the most committed MK precursors. Finally, RGS18 deficiency was correlated to a defect of platelet recovery in vivo under acute conditions of thrombocytopenia. Thus, we highlight a role for RGS18 in platelet generation and function, and provide additional insights into the physiology of RGS18.


Assuntos
Megacariócitos/metabolismo , Ativação Plaquetária/fisiologia , Proteínas RGS/genética , Proteínas RGS/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Contagem de Células Sanguíneas , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Filogenia , Ativação Plaquetária/genética , Regiões Promotoras Genéticas/genética , Serotonina/sangue , Transdução de Sinais/genética , Trombose/metabolismo
2.
J Med Chem ; 57(17): 7293-316, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25075638

RESUMO

In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.


Assuntos
Indóis/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2/farmacologia , Piridazinas/farmacologia , Receptores Purinérgicos P2Y12/metabolismo , Síndrome Coronariana Aguda/prevenção & controle , Difosfato de Adenosina/farmacologia , Administração Oral , Animais , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Humanos , Indóis/síntese química , Indóis/metabolismo , Injeções Intravenosas , Masculino , Modelos Químicos , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/metabolismo , Antagonistas do Receptor Purinérgico P2/síntese química , Antagonistas do Receptor Purinérgico P2/metabolismo , Piridazinas/síntese química , Piridazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y12/genética , Trombose/prevenção & controle
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