RESUMO
A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftiridinas/síntese química , Naftiridinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/química , Técnicas de Química Combinatória , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Naftiridinas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-AtividadeRESUMO
Abstract Sudden cardiac death (SCD) is the leading cause of death during exercise. While initial reports suggested that the most common cause of SCD in young athletes was due to hypertrophic cardiomyopathy (HCM), a critical review of investigations in several populations (athletes, non-athletes, military, national, and international) supports that the most common finding at autopsy of young individuals with SCD is actually a structurally normal heart (SNH). This information is vital for sports medicine clinicians, especially with regard to the pre-participation evaluation (PPE) since cardiac death associated with a SNH is likely attributed to disorders such as arrhythmia or ion channel diseases. This comprehensive review explores the causes of SCD, along with the symptoms preceding death, which ultimately may help refine the PPE and maximize the ability to detect potentially lethal disease prior to competition.