RESUMO
Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague-Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.
Assuntos
Hiperglicemia/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Glucagon/antagonistas & inibidores , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Glicogenólise/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Camundongos Obesos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Following our previous publication describing the biological profiles, we herein describe the structure-activity relationships of a core set of quinoxalines as the hGLP-1 receptor agonists. The most potent and efficacious compounds are 6,7-dichloroquinoxalines bearing an alkyl sulfonyl group at the C-2 position and a secondary alkyl amino group at the C-3 position. These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor.
Assuntos
Receptores de Glucagon/agonistas , AMP Cíclico/metabolismo , Inibidores da Dipeptidil Peptidase IV , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Indicadores e Reagentes , Conformação Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.
