BPI-3016, a novel long-acting hGLP-1 analogue for the treatment of Type 2 diabetes mellitus. (August 2017)

• Record Type: Journal Article
• Authors: Ding, Lieming; Lu, Sisi; Wang, Yanping; Chen, Haibo; Long, Wei; Ma, Cunbo; He, Erlong; Yan, Dan; Tan, Fenlai
• Is Part Of: Pharmacological research. Volume 122(2017:Aug.)
• Page Start: 130
• Page End: 139
• Publication Date: 2017-08
• Subjects: NN9535 (PubChem CID: 56843331) -- Liraglutide (PubChem CID: 16134956) -- Exenatide LAR (PubChem CID: 45588096); BPI-3016 -- Type 2 diabetes -- Long-acting GLP-1 analogues; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2017.05.007
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Glucagon-like peptide-1 (GLP-1) analogues have been commonly used as add-on medications for patients with Type 2 diabetes mellitus (T2DM). Currently, the development of long-acting GLP-1 analogues which allow the freedom and flexibility of once-weekly injections while maintaining their potency for a relatively long period has become the mainstream. Here, we successfully developed a long-acting human GLP-1(7–37) analogue (BPI-3016) with significantly extended half-life and increased resistance to dipeptidyl peptidase IV (DPP-IV) cleavage by structural modifications of human GLP-1. In vitro activity of BPI-3016 including GLP-1 receptor affinity and stimulation of cyclic adenosine monophosphate (cAMP) production was measured. In vivo activity of BPI-3016 such as its effects on glycemic control, β-cell mass and body weight was evaluated in ob/ob mice, db/db mice, and spontaneous diabetic cynomolgus monkeys. The results indicated that BPI-3016 preserved receptor affinity to GLP receptors, and was capable of stimulating cAMP production. In in vivo pharmacokinetic study, the half-life of BPI-3016 was more than 95 h after single dosing in diabetic cynomolgus monkeys. Also, BPI-3016 reduced fasting and post-prandial plasma glucose levels for up to a week after a single dose; It reduced body mass index (BMI), body fat, improved glucose tolerance and showed insulinotropic effects after once-weekly injection for 7 weeks. In conclusion, BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, making it a promising therapy for type 2 diabetes with once-weekly treatment in the clinic.