DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes

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• 作者：Mi-Kyung Kim ; Yu Na Chae ; Ha Dong Kim ; Eun Kyoung Yang ; Eun Jung Cho ; Song-hyen Choi ; Ye-Hwang Cheong ; Hae-Sun Kim ; Heung Jae Kim ; Yeong Woo Jo ; Moon-Ho Son ; Soon-Hoe Kim ; Chang Yell Shin ; ^{pharm91@donga.co.kr}
• 关键词：Dipeptidyl peptidase 4 inhibitor ; DA-1229 ; Glucagon-like peptide-1 ; Insulin resistance ; High fat diet-fed mice ; Db/db mice ; Onset of diabetes
• 刊名：Life Sciences
• 出版年：2012
• 出版时间：2 January 2012
• 年：2012
• 卷：90
• 期：1-2
• 页码：21-29
• 全文大小：747 K

文摘

Aim

To characterize the pharmacodynamic profile of DA-1229, a novel dipeptidyl peptidase (DPP) 4 inhibitor.

Main methods

Enzyme inhibition assays against DPP4, DPP8 and DPP9. Antidiabetic effects of DA-1229 in HF-DIO mice and young db/db mice.

Key findings

DA-1229 was shown to potently inhibit the DPP4 enzyme in human and murine soluble forms and the human membrane-bound form with IC₅₀ values of 0.98, 3.59 and 1.26 nM, respectively. As a reversible and competitive inhibitor, DA-1229 was more selective to human DPP4 (6000-fold) than to human DPP8 and DPP9. DA-1229 (0.1-3 mg/kg) dose-dependently inhibited plasma DPP4 activity, leading to increased levels of plasma GLP-1 and insulin, and thereby lowering blood glucose levels in mice. In high fat diet-fed (HF) mice, a single oral dose of 100 mg/kg of DA-1229 reduced plasma DPP4 activity by over 80 % during a 24 h period. Long-term treatment with DA-1229 for 8 weeks revealed significant improvements in glucose intolerance and insulin resistance, accompanied by significant body weight reduction. However, it remains unclear whether there is a direct causal relationship between DPP4 inhibition and body weight reduction. In young db/db mice, the DA-1229 treatment significantly reduced blood glucose excursions for the first 2 weeks, resulting in significantly lower levels of HbA1c at the end of the study. Furthermore, the pancreatic insulin content of the treatment group was significantly higher than that of the db/db control.

Significance

DA-1229 as a novel and selective DPP4 inhibitor improves the insulin sensitivity in HF mice and delays the onset of diabetes in young db/db mice.