Lixisenatide Acetate

GLP-1R

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2

4858.49

Water：50 mg/mL (9.58 mM)

White powder

Lixisenatide protects Ins-1 cells (a rat-derived β-cell line) from both lipid- and cytokine-induced apoptosis. More importantly, Lixisenatide also prevents lipotoxicity-induced insulin depletion in human islets and preserves insulin production, storage and pancreatic β-cell function in vitro. Binding studies in CHO-K1 cells overexpressing the human GLP-1 receptor show that Lixisenatide is a very potent and selective GLP-1 receptor agonist--the binding affinity of Lixisenatide (Ki = 1.33 ± 0.22 nM) is ∼ 4-times greater than that of human GLP-1 (Ki = 5.09 ± 1.19 nM). In more than 80 different binding assays, lixisenatide does not exhibit any relevant interaction with other potential drug targets, confirming its high selectivity for the GLP-1 receptor.

The half-life of lixisenatide is 2-4 hours, and it is classed as a short-acting GLP-1-receptor agonist, compared with the long-acting GLP-1-based peptides, liraglutide and albiglutide. Lixisenatide can significantly improve glucose-stimulated insulin secretion. In healthy normoglycemic dogs, single subcutaneous injections of lixisenatide produces dose-dependent reductions in plasma glucose after an oral glucose challenge and significantly reduces postprandial glucose excursions by 67% compared with placebo without increasing insulin concentrations. The effect of lixisenatide on postprandial blood glucose excursions in dogs is, at least in part, related to inhibition of gastric emptying and delayed intestinal glucose absorption. Dose-dependent reductions in plasma glucose after an oral glucose challenge have also been demonstrated in both the db/db mouse and ZDF rat. Importantly, this activity is glucose-dependent with no effect at physiological glucose concentrations. In db/db mice, chronic lixisenatide administration preventes the progressive deterioration in glucose tolerance observed in control animals and is associated with significant dose-dependent reductions in glycosylated hemoglobin (HbA1c). In ZDF rats, a continuous subcutaneous infusion of lixisenatide 50 μg/kg/day for 12 weeks significantly decreases basal blood glucose and improves oral glucose tolerance compared with control animals. It has no hypoglycemic effect and does not change HbA1c in normoglycemic rats. Lixisenatide can maintain beta cell mass and function through stimulation of islet cell proliferation and neogenesis, and inhibition of islet cell apoptosis. Lixisenatide preserves pancreatic responsiveness in diabetic animals.

Synthetic

醋酸利西拉来

C₂₁₅H₃₄₇N₆₁O₆₅S.6C₂H₄O₂

1997361-87-1；320367-13-3（free base）