ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
This article is part of the Research TopicPolysaccharides and Peptides from Functional Foods in Diabetes Management: Pathways, Mechanisms, and Computational InsightsView all articles
Preclinical pharmacological profiles of cofrogliptin, a novel and bi-weekly DPP-4 inhibitor
Provisionally accepted
- Haisco Pharmaceutical Group Comp. Ltd., Chengdu, China
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Objective: DPP-4 inhibitors are now established agents for glycaemic control in diabetes. Herein, this study systematically characterized cofrogliptin and elucidated its pharmacology, pharmacokinetics, and therapeutic efficacy for type 2 diabetes. Methods: In vitro pharmacological characterization of cofrogliptin was performed using recombinant enzyme inhibition assays, serum/plasma DPP-4 inhibitory activity profiling, and the SafetyScreen panel. In vivo DPP-4 inhibitory potency was evaluated via measurement of serum DPP-4 activity in ICR and ob/ob mice following a single oral administration of cofrogliptin. Additionally, the oral glucose tolerance test was conducted in ICR and db/db mice pre-treated with a single oral dose of cofrogliptin. For assessment of chronic therapeutic efficacy, ob/ob mice were used with intermittent dosing to simulate prolonged diabetes management. Finally, a translational pharmacokinetic-pharmacodynamic relationship was established across rats, dogs, and monkeys to elucidate the mechanistic basis of cofrogliptin’s long-acting therapeutic benefits. Results: The findings have revealed that cofrogliptin is a potent and selective DPP-4 inhibitor with an IC50 of 10.80 nM in the recombinant DPP-4 enzyme assay. In ob/ob mice, it exerted favorable anti-diabetic effects, superior to those of MK3102. Furthermore, cofrogliptin exhibited a robust PK-PD relationship across rats, dogs, and monkeys. Notably, following a single oral dose of 10 mg/kg cofrogliptin, monkeys exhibited sustained DPP-4 inhibition of approximately 80% through day 14. Specifically, cofrogliptin exhibited superior pharmacokinetic profiles compared to MK3102 in rodents, whereas its PK characteristics in non-rodents were comparable to those of MK3102. Based on allometric scaling analyses, cofrogliptin is predicted to display superior human pharmacokinetic properties relative to MK3102, with anticipated longer-acting features that align with its clinical dosing frequency. Conclusions: Consequently, as the only approved bi-weekly DPP-4 inhibitor, cofrogliptin is well-positioned to substantially improve medication adherence among patients with type 2 diabetes, thereby improving therapeutic outcomes.
Keywords: type 2 diabetes, Dipeptidyl Peptidase 4, DPP-4 inhibitor, cofrogliptin, HSK7653, Long-acting, bi-weekly
Received: 09 Sep 2025; Accepted: 08 Dec 2025.
Copyright: © 2025 Gou, Dou, Tang, Zheng, Zhang, Wang, Meng and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ju Wang
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