RESUMO
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.
Assuntos
Aminas/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
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.
Assuntos
Quinolinas/síntese química , Receptores do FSH/antagonistas & inibidores , Animais , Linhagem Celular , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Camundongos , Peso Molecular , Quinolinas/química , Quinolinas/farmacologia , Ratos , Receptores do FSH/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Técnicas de Química Combinatória/métodos , Receptores do FSH/agonistas , Receptores do FSH/química , Receptores do FSH/metabolismoRESUMO
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.