RESUMO
The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.
Assuntos
Pirazinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Tecido Adiposo/metabolismo , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Injeções Intraventriculares , Masculino , Microssomos Hepáticos/metabolismo , Atividade Motora/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Restrição Física , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Sítios de Ligação , Química Farmacêutica/instrumentação , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
