G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges

Abstract

In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development.

ZB-16, a Novel GPR119 Agonist, Relieves the Severity of Streptozotocin–Nicotinamide-Induced Diabetes in Rats

“…This stage of the current study was to assess the effects of ZB-16 on the secretion of incretins and insulin, the well-known action mechanism of GPR119 agonists (4). The insulin secretion undergoes several stages following the GLP-1 secretion.…”

“…Since a number of specific receptors (GPR40, GPR41, GPR43, GPR119, and GPR120) expressed on the enteroendocrine L- and K-cells were discovered, there has been an increasing interest in making new effective drugs to treat type 2 diabetes mellitus and metabolic syndrome (4). Leading pharmaceutical companies (Arena Pharmaceuticals, GlaxoSmithKline, Sanofi, Astellas, etc.)…”

Synthesis and biological evaluation of 1, 2, 4‐oxadiazole derivatives as novel GPR119 agonists

“…GPR119 is highly expressed in pancreatic β cells, pancreatic polypeptide‐secreting cells in mouse and rat islets as well as gastrointestinal tract . In pancreatic β‐cell line, activation of GPR119 results in the formation of intracellular cAMP . GPR119 might be a superior target for the therapy of type 2 diabetes mellitus.…”

“…Several phospholipids and lipid amides have been identified as endogenous GPR119 agonists, including oleoylethanolamide (OEA), N ‐oleoyldopamine (OLDA), and 2‐oleoylglycerol (2‐OG) . However, these molecules are low active at GPR119 in cellular assays and often effective on other receptors that are involved in metabolism, which leads to a discussion about whether these compounds are the ‘true’ endogenous ligands in a particular tissue . In recent years, there have been an increasing number of GPR119 agonists for treatment of type 2 diabetes mellitus (Figure ).…”

“…MBX2982 and GSK1292263 exhibited potent potency of GPR119 activation . However, the clinical research of GSK1292263 has been broke off, as well as several other clinical candidates, without disclosure the root causes, and MBX2982 has been outlicensing …”