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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
G protein-coupled receptors (GPCRs) superfamily is formed by several receptors involved in the detection of a wide range of chemicals (nutrients, hormones, neurotransmitters, odorants or tastants), and is the largest family of membrane receptors in humans and numerous other species, as well as the largest family of targets for approved drugs (Sriram and Insel, 2018); specifically for antidiabetic drugs, GLP-1 receptors and GPR119 are the most studied (Reimann and Gribble, 2016), and will be discussed in the following sections.
Protecting Pancreatic β-cells from Metabolic Insults
Published in Christophe Wiart, Medicinal Plants in Asia for Metabolic Syndrome, 2017
Hexane extract of Angelica dahurica (Fisch.) Benth. & Hook. f. (Figure 2.17) given at a single oral dose of 300 mg/kg given to C56BL6 mice lowered 30 minutes peak glycemia in oral glucose tolerance test and increased plasma insulin.261 From this extract, imperatorin and phellopterin (Figure 2.18) at a concentration of 100 µM increased the reporter activity in GPR119-CRE-bla CHO-K1 cells, increased glucagon-like peptide-1 secretion in GLUTag cells and increased glucose-stimulated insulin secretion in INS-1 cells.261 This suggests the ability of these furanocoumarins to stimulates G-protein-coupled receptor 119 (GPR119) expressed in pancreatic β-cells and intestinal endocrine L-cells to promote glucose-stimulated insulin secretion and glucagon-like peptide-1 release.261 Clinical trials are warranted.
GPR119 agonists for the treatment of type 2 diabetes: an updated patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Huilan Li, Yuanying Fang, Shuchun Guo, Zunhua Yang
GPR119 is a class A (rhodopsin-type) G protein-coupled receptor identified in several vertebrate species, including mouse, rat, zebrafish, monkey, dog and humans [10]. The human GPR119 is encoded by a single exon gene located on the short arm of chromosome X (Xp26.1) and is comprised of 335 amino acids [11,12]. GPR119 is expressed on certain enteroendocrine L and K cells in the small intestine and β cells within the islets of Langerhans of the pancreas as well [13,14]. The stimulation of GPR119 by an agonist can lead to a rise in the level of cAMP, and then trigger the release of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) or insulin from L, K and β cells [15,16]. Thus, GPR119 agonist will influence both the secretory activity and the viability of β-cells, and improve the glucose homeostasis in patients with T2DM [17,18]. A recent rodent pharmacological study from Merck also reveals that the activation of GPR119 might increase glucagon secretion to alleviate the occurrence of hypoglycemia [18].
Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Yuanying Fang, Shaokun Zhang, Min Li, Lijuan Xiong, Liangxing Tu, Saisai Xie, Yi Jin, Yanhua Liu, Zunhua Yang, Ronghua Liu
G protein-coupled receptor 119 (GPR119) is a member of class A (rhodopsin-type) GPCR family, with highly expressed in pancreatic β-cells and the K and L cells of the gastrointestinal tract7–9. Activation of GPR119 increases the intracellular cyclic AMP (cAMP) level, which in turn directly stimulate the glucose-dependent insulin secretion and regulate glucagon-like peptide 1 (GLP-1), leading to improve the glucose tolerance in T2DM patients10–14. In addition, GPR119 agonists showed β-cells function preservation, which is also an important role in current T2DM therapy15–17. As a result, GPR119 agonists are used for discovery of anti-T2DM agents by lowering the blood glucose level and improving β-cells function. Indeed, numerous synthetic, small molecule GPR119 agonists were revealed by academia and industry to date, and some of which have advanced into clinical trials such as MBX-2982, BMS-903452, LEZ763, ZYG-1918–30. Despite tremendous endeavours, none of GPR119 agonists were approved to market by FDA up to now.
In vivo multiple metabolic pathways for a novel G protein-coupled receptor 119 agonist DS-8500a in rats: involvement of the 1,2,4-oxadiazole ring-opening reductive reaction in livers under anaerobic conditions
Published in Xenobiotica, 2019
Chie Makino, Akiko Watanabe, Tsuneo Deguchi, Hideyuki Shiozawa, Ilona Schreck, Veronika Rozehnal, Tomoko Ishizuka, Nobuaki Watanabe, Osamu Ando, Norie Murayama, Hiroshi Yamazaki
G protein-coupled receptor 119 (GPR119) expressed in L-cells of intestines and β-cells of the pancreas (Odori et al., 2013) reportedly stimulates glucagon-like peptide-1 secretion, regulates glycemic control in intestinal L-cells (Chu et al., 2008), and directly induces glucose-stimulated insulin secretion in pancreatic β-cells (Chu et al., 2007). These dual activities of GPR119 improve glucose homeostasis in type 2 diabetes mellitus patients. A novel agonist DS-8500a, 4-(5-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(2R)-1-hydroxypropan-2-yl]benzamide (Figure 1), was developed for treating type 2 diabetes mellitus, with an agonistic activity in recombinant human GPR119 and to improve glucose tolerance in Zucker fatty rats (Matsumoto, 2016). DS-8500a was effective in safely improving glycemic and lipid profiles in the clinical phase II study with high tolerance in Japanese type 2 diabetes patients (Inagaki et al., 2017).