RESUMEN
Substituted 6-amino-4-phenyl-tetrahydroquinoline derivatives are described that are antagonists for the G(s)-protein-coupled human follicle-stimulating hormone (FSH) receptor. These compounds show high antagonistic efficacy in vitro using a CHO cell line expressing the human FSH receptor. Antagonist 10 also showed a submicromolar IC(50) in a more physiologically relevant rat granulosa cell assay and was found to significantly inhibit follicle growth and ovulation in an ex vivo mouse model. This compound class may open the way toward a novel, nonsteroidal approach for contraception.
Asunto(s)
Quinolinas/síntesis química , Receptores de HFE/antagonistas & inhibidores , Animales , Línea Celular , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Ratones , Peso Molecular , Quinolinas/química , Quinolinas/farmacología , Ratas , Receptores de HFE/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
High-throughput screening of two million compounds in 37 distinct encoded combinatorial libraries using FSH receptor transfected cells provided small molecule agonists such as 1 (EC(50)=3 microM) and 2 (EC(50)=3.9 microM), based on which a focused combinatorial library with a total of 31372 compounds was designed, synthesized, and screened to reveal 72 novel biaryl FSH receptor agonists such as 8a-c as well as a unique combinatorial SAR.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Receptores de HFE/agonistas , Receptores de HFE/química , Receptores de HFE/metabolismoRESUMEN
Potent small molecule biaryl diketopiperazine FSH receptor agonists such as 10c (EC(50)=13 nM) and 11f (EC(50)=1.2 nM) were discovered through the design, synthesis and evaluation of three biaryl diketopiperazine optimization libraries with over 300 compounds. These libraries were prepared via solid-phase parallel synthesis using a cyclization-release method.