RESUMO
Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5RESUMO
Modulation of the metabotropic glutamate subtype 5 (mGlu5) receptor may be useful in the treatment of a variety of central nervous system disorders. Herein, we report on the discovery, synthesis, and biological evaluation of dipyridyl amines as small molecule mGlu5 antagonists.
Assuntos
Aminas/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Aminas/farmacocinética , Aminas/farmacologia , Animais , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
The mGlu5 receptor has been implicated in a number of CNS disorders. Herein, we report on the discovery, synthesis, and biological evaluation of dipyridyl amides as small molecules mGluR5 antagonists.
Assuntos
Amidas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
The SAR of the lead compounds 2a and 2b was rapidly explored. Utilizing a parallel solution-phase Suzuki coupling approach, in tandem with strong cation exchange resin (SCX) purification afforded the desired focused library. The library was evaluated in vitro, a ninefold potency increase was achieved and the preference for ortho substitution of moderate steric bulk of the fourth, phenyl ring was identified. In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach.
Assuntos
Isoxazóis , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Técnicas de Química Combinatória/métodos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Estrutura Molecular , Receptor de Glutamato Metabotrópico 5 , Soluções/química , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.