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1.
J Med Chem ; 52(14): 4173-91, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19552437

RESUMO

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.


Assuntos
Pirazinas/química , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Macaca fascicularis , Masculino , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 14(6): 1483-6, 2004 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-15006386

RESUMO

Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.


Assuntos
Butadienos/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nitrilas/síntese química , Animais , Células COS , Chlorocebus aethiops , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Relação Estrutura-Atividade
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