RESUMEN
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
Asunto(s)
Aminas/química , Isoquinolinas/química , Inhibidores de Proteínas Quinasas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Aminas/síntesis química , Aminas/farmacocinética , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
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.