factory 204656-20-2 Liraglutide in China CAS NO.204656-20-2

 

Liraglutide Usage And Synthesis

Overview Type 2-diabetes mellitus(T2DM) is a progressive disease associated with significant morbidity and mortality. Glucagon like peptide-1(GLP-1) is an incretin hormone secreted from the small intestine that lowers fasting and postprandial glucose through multiple mechanisms including glucose-dependent insulin secretion, reduction of glucagon secretion, delaying gastric emptying and increased satiety[1-4]. Liraglutide, a human glucagon-like peptide 1(GLP-1) analogue is a treatment for T2DM that is administered as a once-daily subcutaneous injection. Liraglutide is a GLP-1 analog in which lysine at position 34 has been replaced with arginine, and palmitic acid has been attached via glutamoyl spacer to lysine at position 26[1-4]. No animal-derived raw materials or excipients are used in the production of liraglutide. The drug product is a solution for subcutaneous injection containing 6.0 mg/ml of the drug substance presented in a pre-filled, multi-dose pen-injector. Unlike GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in human suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption, binding to albumin and stability toward the DPP-4 enzyme both resulting in a prolonged plasma half-life. The analog is produced as the polypeptide precursor by r-DNA technology with Saccharomyces cerevisiae strain YES2085 as the production strain. The peptide is acylated with a fatty acid chain during down-stream processing[1-4].

 

Figure 1 the chemical structure of Liraglutide 

Liraglutide is a long-acting GLP-1 analog, designed to bind to albumin as the main molecular mechanism of protraction[1-4]. In vitro, this was shown in the receptor cAMP as well as binding assay where addition of albumin shifted the dose-response and/or binding curve to the right. The apparent reduced potency of liraglutide underlines that only the free fraction of liraglutide is responsible for its pharmacological effect in vitro as well as in vivo. Furthermore, liraglutide in a pharmaceutical solution forms a micell-like heptamer that may contribute to the slow absorption from the subcutis[1-4]. Liraglutide is a potent, selective and efficacious agonist on the human as well as mouse, rat, rabbit, pig and Cynomolgus monkey GLP-1 receptor. Liraglutide has been shown to exert a number of actions in vitro that are known to be specific GLP-1 effects[1-4]. Liraglutide has also been shown stimulate insulin secretion from isolated β-cell islets in a glucose-dependent manner in vitro. Liraglutide-attenuated β-cell apoptosis in vitro under adverse conditions with high concentrations of free fatty acids and proinflammatory cytokines. Moreover, a proliferative effect on primary rat β-cells was demonstrated for liraglutide in vitro whereas no consistent effect was observed under hyperglycemic conditions in vivo[1-4].