RESUMEN
OBJECTIVE: The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. RESEARCH DESIGN AND METHODS: Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. RESULTS: Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. CONCLUSIONS: These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization.
Asunto(s)
Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Receptores de Glucagón/genética , Animales , AMP Cíclico/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Genes Reporteros , Glucagón/farmacología , Péptido 1 Similar al Glucagón/fisiología , Receptor del Péptido 1 Similar al Glucagón , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Luciferasas/genética , Masculino , Hormona Paratiroidea/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/agonistas , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl-D-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue. A number of modifications resulted in enhanced potency over the parent benzyl-D-Ser-AIB derivative.
