Abstract
Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance and defective insulin secretion[1, 2]
By targeting dipeptidyl peptidase-4 (DPP4) and G protein-coupled receptor 119 (GPR119), it was designed by combining pharmacophores of GPR119 agonists and the DPP4 inhibitor, linagliptin, via a linker[19] (Fig. 1A)
Our results showed that the IC50 of HBK001 and linagliptin was 66 nM and 0.75 nM respectively (Fig. 1B)
Summary
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance and defective insulin secretion[1, 2]. GLP-1 secretion can be enhanced by activating some G-protein coupled receptors (GPRs), such as GPR119, which is highly expressed in both pancreatic β-cells[13] and intestinal enteroendocrine L cells[14]. It is reported that GPR119 activation in L cells triggers GLP-1 release and GLP-1 receptor activation, which stimulates glucose-dependent insulin secretion (GSIS) in β-cells. Previous studies have shown that some diabetic individuals exhibit GLP-1 deficiency[16] but DPP4 inhibitors fail to effectively promote islet β-cell survival in these cases[17]. We report a newly-developed compound, (R)-8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl1-(3-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperazin-1-yl)propyl)-1H-purine-2,6 (3H, 7H)-dione (named HBK001 hereafter), which is digitally-designed and synthesized according to our previous work on combinatory strategies of DPP4 inhibitors and GPR119 agonists[19,20,21]. We hypothesize that HBK001 could both inhibit GLP-1 degradation and induce GLP-1 production by targeting DPP4 and GPR119 simultaneously ex and in vivo
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
