RESUMO
In the course of a programme aimed at discovering new ligands of the estrogen receptor, we explored a series of substituted biphenyls. Their synthesis and binding affinity are described.
Assuntos
Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Esteroides/química , Receptor alfa de Estrogênio , Humanos , Proteínas Recombinantes/efeitos dos fármacosRESUMO
A new family of non-steroidal 5-alpha-reductase inhibitors was designed by replacing the steroid skeleton of an inhibitor related to estrone by a biphenyl moiety. This hypothesis originated from the reported estrogenic activity of a few biphenyl compounds (see Part 1 of this paper; Lesuisse et al. Bioorg. Med. Chem. Lett. 2001, 11, 1709). Two compounds turned out to be potent type 2 5-alpha-reductase inhibitors with IC(50)'s of inhibition in the nanomolar range. These are to our knowledge amongst the most potent non-steroidal 5-alpha-reductase inhibitors described to date.
Assuntos
Inibidores de 5-alfa Redutase , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Esteroides/química , Inibidores Enzimáticos/química , Relação Estrutura-AtividadeRESUMO
During the course of a study aimed at the search for new potent aromatase inhibitors, several new androstenedione analogs were synthesized and evaluated. This study led to the discovery of 19-[(methylthio)methyl]androsta-4,9(11)-diene-3,17-dione (7; RU54115) already described by our laboratory. The object of the present series of papers is to disclose the result of the structure-activity relationship studies that gave rise to this compound. This first part deals mainly with the substitution in the 19-position of the steroid nucleus. Several parameters were varied, the length of the chain and its rigidity and branching, as well as the nature of the heteroatom itself and its substitution. The interaction of these new compounds with human placental aromatase in competition with the substrate androstenedione was studied by difference visible spectroscopy. The in vivo aromatase-inhibiting activities were evaluated by measuring the estradiol lowering after oral administration of the compounds to PMSG-primed female rats.
Assuntos
Inibidores da Aromatase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrenos/síntese química , Estrenos/farmacologia , Esteroides/farmacologia , Animais , Aromatase/isolamento & purificação , Estrenos/química , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Microssomos/enzimologia , Placenta/enzimologia , Ratos , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
A series of new 4-(alkylthio)-substituted androstenedione analogues was designed as potential suicide inhibitors of aromatase on the basis of mechanistic considerations on the mode of action of the enzyme. Their synthesis and biological evaluation are described. Among the most interesting are the 4-[(difluoromethyl)thio]-, 4-[(fluoromethyl)thio]-, and 4-[(chloromethyl)thio]androstenediones 12, 13, and 14 with respective IC50's of 2.7, 0.8, and 0.94 microM. Compound 12 was a reversible inhibitor of aromatase while compounds 13 and 14 displayed time-dependent kinetics of inhibition with respective KI's and half-times of inactivation of 30 nM and 3.75 min for 13 and 30 nM and 3 min for 14. The inhibition of aromatase by 14 was NADPH-dependent, and was protected by the presence of substrate (0.5-1 microM), while beta-mercaptoethanol (0.5 mM) failed to protect the enzyme from inactivation. Dialysis failed to reactivate aromatase previously inactivated by 14. The mechanistic implications of these findings are discussed.
Assuntos
Androstenodiona/análogos & derivados , Inibidores da Aromatase , Androstenodiona/síntese química , Androstenodiona/farmacologia , Animais , Feminino , Humanos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Placenta/efeitos dos fármacos , Placenta/enzimologia , Placenta/ultraestrutura , Gravidez , Ratos , Ratos EndogâmicosRESUMO
RU54115 is a new potent inhibitor of aromatase. In vitro, it inhibits the enzyme from human placental microsomes with a Ki of 0.5 nM, which places it among the tightest reported steroidal inhibitors of aromatase. In vivo, it lowers the amount of circulating estradiol in pregnant mare serum gonadotrophin (PMSG)-primed female rats with an ED50 of 0.4 mg/kg when given s.c. and 4 mg/kg when given orally. An oral dose of 25 mg/kg when given once daily to female rats was able to inhibit the growth of DMBA-induced mammary tumors.