1.
Bioorg Med Chem Lett
; 22(23): 7223-6, 2012 Dec 01.
Artigo
em Inglês
| MEDLINE
| ID: mdl-23084894
RESUMO
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiofenos/química , Administração Oral , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Pirimidinonas/síntese química , Pirimidinonas/uso terapêutico , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/uso terapêutico
2.
Bioorg Med Chem Lett
; 22(4): 1575-8, 2012 Feb 15.
Artigo
em Inglês
| MEDLINE
| ID: mdl-22266036
RESUMO
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.