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J Med Chem ; 50(1): 113-28, 2007 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-17201415

RESUMO

A weak human glucagon receptor antagonist with an IC50 of 7 microM was initially found by screening of libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor. Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead were identified and used to further optimize this series with respect to pharmacokinetic properties. This final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was efficacious in lowering blood glucose levels in a diabetic animal model.


Assuntos
Hipoglicemiantes/síntese química , Receptores de Glucagon/antagonistas & inibidores , beta-Alanina/análogos & derivados , beta-Alanina/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Humanos , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Obesos , Ratos , Relação Estrutura-Atividade , beta-Alanina/farmacologia
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