RESUMO
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Pirimidinonas/farmacologia , Renina/antagonistas & inibidores , Administração Oral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Iminas/síntese química , Iminas/química , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A total synthesis of the racemic natural product tylophorine [(+/-)-1] has been demonstrated using the palladium-catalyzed carboamination method developed by Wolfe and co-workers. In this case, an electron-rich aryl bromide 18 was prepared in four steps and subjected to palladium-catalyzed Wolfe carboamination conditions with olefinic carbamate 7 to provide the racemic 2-(arylmethyl)pyrrolidine (+/-)-19 in good yield and was further elaborated to racemic tylophorine. This application of the Wolfe carboamination protocol as a key step to construct a natural product provides further evidence of the utility of the method.
Assuntos
Alcaloides/síntese química , Antineoplásicos Fitogênicos/síntese química , Carbamatos/química , Indolizinas/síntese química , Paládio/química , Fenantrenos/síntese química , Alcaloides/química , Alcenos/química , Aminação , Antineoplásicos Fitogênicos/química , Catálise , Hidrocarbonetos Bromados/química , Hidrocarbonetos Cíclicos/química , Indolizinas/química , Modelos Químicos , Fenantrenos/química , Pirrolidinas/química , EstereoisomerismoRESUMO
The first discrete, self-complementary, quadruply hydrogen-bonded complexes based on the 2,6-diaminopurine (DAP) scaffold have been prepared; regioselective urea formation at the C2 amino group of the heterocycle allows intermolecular dimerization (K(dim) approximately 1-1.6 x 10(3) M(-1) in CDCl3) through a DADA hydrogen bonding motif.