RESUMO
The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
Assuntos
Quinolinas/farmacologia , Receptores de Progesterona/agonistas , Animais , Ligação Competitiva , Feminino , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Útero/metabolismoRESUMO
Torquoselectivity in the electrocyclic interconversions of 1-azapolyenes and their heterocyclic isomers was investigated theoretically. The ring openings of 1,2-dihydroazete, 1,2-dihydropyridine, and 1,2-dihydroazocine were examined using HF, MP2, and B3LYP calculations. A large preference for inward rotation of the nitrogen lone pair and outward rotation of the N-H group was found for the four- and six-electron systems. No strong preference was observed for the eight-electron system.