RESUMO
Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.
Assuntos
Benzoxazinas/síntese química , Oxazinas/síntese química , Pirróis/síntese química , Receptores de Progesterona/agonistas , Tionas/síntese química , Fosfatase Alcalina/metabolismo , Animais , Área Sob a Curva , Benzoxazinas/química , Benzoxazinas/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Anticoncepcionais Femininos/síntese química , Anticoncepcionais Femininos/química , Anticoncepcionais Femininos/farmacologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Feminino , Meia-Vida , Humanos , Técnicas In Vitro , Ligantes , Estrutura Molecular , Oxazinas/química , Oxazinas/farmacologia , Estrutura Terciária de Proteína , Pirróis/química , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/química , Relação Estrutura-Atividade , Tionas/química , Tionas/farmacologiaRESUMO
A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively).
Assuntos
Benzoxazinas/farmacologia , Indóis/farmacologia , Pirróis/química , Receptores de Progesterona/efeitos dos fármacos , Benzoxazinas/química , Indóis/químicaRESUMO
A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this communication, the synthesis and structure-activity relationships (SARs) of various 3,3-substituents are discussed where it is clear that small alkyl and spiroalkyl groups are required to achieve better PR antagonist activity.