1.
Bioorg Med Chem Lett
; 22(12): 3873-8, 2012 Jun 15.
Artigo
em Inglês
| MEDLINE
| ID: mdl-22608962
RESUMO
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Oxidiazóis/síntese química , Animais , Diabetes Mellitus/tratamento farmacológico , Diacilglicerol O-Aciltransferase/metabolismo , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Ligantes , Camundongos , Obesidade/tratamento farmacológico , Oxidiazóis/farmacocinética , Relação Quantitativa Estrutura-Atividade , Ratos
2.
Bioorg Med Chem Lett
; 16(21): 5567-71, 2006 Nov 01.
Artigo
em Inglês
| MEDLINE
| ID: mdl-16945526
RESUMO
Two series of novel thienopyrrole inhibitors of recombinant human liver glycogen phosphorylase a (GPa) which are effective in reducing glucose output from rat hepatocytes are described. Representative compounds have been shown to bind at the dimer interface site of the rabbit muscle enzyme by X-ray crystallography.