RESUMO
A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.
Assuntos
Anti-Hipertensivos/síntese química , Antagonistas de Receptores de Mineralocorticoides , Nitrilas/síntese química , Piridinas/síntese química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Masculino , Modelos Moleculares , Nitrilas/farmacocinética , Nitrilas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A number of known 1,4-dihydropyridine CCBs were identified as having comparable potency to the steroidal MR antagonist eplerenone. Chiral resolution of mebudipine revealed that MR and CCB activity reside in opposite enantiomers. Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine. Molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters.
Assuntos
Di-Hidropiridinas/química , Antagonistas de Receptores de Mineralocorticoides , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Linhagem Celular , Cristalografia por Raios X , Di-Hidropiridinas/farmacologia , Eplerenona , Genes Reporter , Humanos , Luciferases/genética , Modelos Moleculares , Ligação Proteica , Ratos , Receptores de Mineralocorticoides/química , Receptores de Mineralocorticoides/genética , Espironolactona/análogos & derivados , Espironolactona/química , Espironolactona/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Secondary amines are oxidized by the methyltrioxorhenium/hydrogen peroxide system to the corresponding nitrones in excellent yield. The results provide a further example of the parallel between the chemistry of this metal system and that of the dioxiranes.
