Yi Huan
Peking Union Medical College | China
Title: Discovery of GPR119/DPP4 dual-target compounds as anti-diabetic candidates
Biography
Biography: Yi Huan
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 designed and synthesized a series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Among these derivatives, we validate a 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 primary islets in a concentration-dependent manner. A single administration of HBK001 in ICR mice can increase plasma incretins (GLP-1 and GIP) levels much more efficiently than DPP4 inhibitor linagliptin. 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. Furthermore, HBK001 can improve islet morphology in diabetic KKAy mice, increase β-cell mass by promoting proliferation and up-regulating genes involved in β-cell proliferation and function. Thus, we have identified, designed and synthesized a novel GPR119/DPP4 dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors..