RESUMO
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.
Assuntos
Anti-Hipertensivos/síntese química , Arritmias Cardíacas/prevenção & controle , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Piperazinas/síntese química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Feminino , Coração/fisiopatologia , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Macaca fascicularis , Masculino , Técnicas de Cultura de Órgãos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Renina/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
SIGNIFICANCE: This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.
Assuntos
Neoplasias , Humanos , Linhagem Celular TumoralRESUMO
We report a simple, efficient, and stereoselective Mukaiyama aldol approach to install the key hydroxymethyl moiety into the benzazocane framework of FR900482. Synthetic investigations revealed that the reaction is highly dependent upon the electronics of the aromatic ring. This approach enabled the economical introduction of a [13C] label to study the biosynthesis of these structurally and biogenetically related natural products. Epimerization of the initially formed beta-hydroxy ketone may enable access to mitomycin C or FR900482 biosynthetic congeners.
Assuntos
Antineoplásicos/síntese química , Compostos Azo/química , Mitomicina/síntese química , Metilação , Oxazinas/síntese química , EstereoisomerismoRESUMO
[reaction: see text] A diastereoselective total synthesis of securinine in optically pure form was achieved by employing ring-closing metathesis of the corresponding dienyne compound as a key step.
Assuntos
Alcaloides/síntese química , Azepinas/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Lactonas/síntese química , Piperidinas/síntese química , Compostos Heterocíclicos de Anel em Ponte , Modelos Químicos , Estrutura Molecular , Ácidos Pipecólicos/química , EstereoisomerismoRESUMO
Total syntheses of (+)-cytisine, (-)-kuraramine, (-)-isokuraramine, and (-)-jussiaeiine A were achieved via a samarium diiodide-promoted reductive deamination reaction, followed by simultaneous recyclization of a proline derivative to give the corresponding delta-lactam derivative, as a key step.