更新于：2024-11-01

GLP-1R x SCTR

更新于：2024-11-01

基本信息

关联

项与 GLP-1R x SCTR 相关的药物

GUB06-046

靶点

GLP-1R x SCTR

作用机制

GLP-1R激动剂 [+1]

在研机构-

原研机构

Gubra A/S

在研适应症-

非在研适应症

2型糖尿病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GLP-1R x SCTR 相关的临床结果

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100 项与 GLP-1R x SCTR 相关的转化医学

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0 项与 GLP-1R x SCTR 相关的专利（医药）

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项与 GLP-1R x SCTR 相关的文献（医药）

2021-03-01·Biochemical Pharmacology2区 · 医学

Discovery of small molecule positive allosteric modulators of the secretin receptor

2区 · 医学

Article

作者: Brown, Brock T ; Harikumar, Kaleeckal G ; Dengler, Daniela G ; Miller, Laurence J ; Shinoki-Iwaya, Aki ; Sergienko, Eduard A ; Pollari, Sirkku ; Sun, Qing ; Ardecky, Robert

The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the treatment of cardiovascular, gastrointestinal, and metabolic disorders. However, no non-peptidic molecules targeting this receptor have yet been disclosed. Using a high-throughput screening campaign directed at SCTR to identify small molecule modulators, we have identified three structurally related scaffolds positively modulating SCTRs. Here we outline a comprehensive study comprising a structure-activity series based on commercially available analogs of the three hit scaffold sets A (2-sulfonyl pyrimidines), B (2-mercapto pyrimidines) and C (2-amino pyrimidines), which revealed determinants of activity, cooperativity and specificity. Structural optimization of original hits resulted in analog B2, which substantially enhances signaling of truncated secretin peptides and prolongs residence time of labeled secretin up to 13-fold in a dose-dependent manner. Furthermore, we found that investigated compounds display structural similarity to positive allosteric modulators (PAMs) active at the glucagon-like peptide-1 receptor (GLP-1R), and we were able to confirm cross-recognition of that receptor by a subset of analogs. Studies using SCTR and GLP-1R mutants revealed that scaffold A, but not B and C, likely acts via two distinct mechanisms, one of which constitutes covalent modification of Cys-347^GLP-1R known from GLP-1R-selective modulators. The scaffolds identified in this study might not only serve as novel pharmacologic tools to decipher SCTR- or GLP-1R-specific signaling pathways, but also as structural leads to elucidate allosteric binding sites facilitating the future development of orally available therapeutic approaches targeting these receptors.

2017-12-01·Journal of Peptide Science4区 · 生物学

GUB06‐046, a novel secretin/glucagon‐like peptide 1 co‐agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice

4区 · 生物学

Article

作者: Vrang, Niels ; Dalbøge, Louise S. ; Pedersen, Søren L. ; van Witteloostuijn, Søren B. ; Jensen, Knud J. ; Jelsing, Jacob ; Jensen, Grethe Vestergaard ; Hansen, Gitte ; Midtgaard, Søren Roi

Bariatric surgery is currently the most effective treatment of obesity, which has spurred an interest in developing pharmaceutical mimetics. It is thought that the marked body weight‐lowering effects of bariatric surgery involve stimulated secretion of appetite‐regulating gut hormones, including glucagon‐like peptide 1. We here report that intestinal expression of secretin is markedly upregulated in a rat model of Roux‐en‐Y gastric bypass, suggesting an additional role of secretin in the beneficial metabolic effects of Roux‐en‐Y gastric bypass. We therefore developed novel secretin‐based peptide co‐agonists and identified a lead compound, GUB06‐046, that exhibited potent agonism of both the secretin receptor and glucagon‐like peptide 1 receptor. Semi‐acute administration of GUB06‐046 to lean mice significantly decreased cumulative food intake and improved glucose tolerance. Chronic administration of GUB06‐046 to diabetic db/db mice for 8 weeks improved glycemic control, as indicated by a 39% decrease in fasting blood glucose and 1.6% reduction of plasma HbA1c levels. Stereological analysis of db/db mice pancreata revealed a 78% increase in beta‐cell mass after GUB06‐046 treatment, with no impact on exocrine pancreas mass or pancreatic duct epithelial mass. The data demonstrate beneficial effects of GUB06‐046 on appetite regulation, glucose homeostasis, and beta‐cell mass in db/db mice, without proliferative effects on the exocrine pancreas and the pancreatic duct epithelium. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

2012-01-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Site of action of a pentapeptide agonist at the glucagon-like peptide-1 receptor. Insight into a small molecule agonist-binding pocket

4区 · 医学

Article

作者: Delia I. Pinon ; Laurence J. Miller ; Maoqing Dong

The development of small molecule agonists for class B G protein-coupled receptors (GPCRs) has been quite challenging. With proof-of-concept that exenatide, the parenterally administered peptide agonist of the glucagon-like peptide-1 (GLP1) receptor, is an effective treatment for patients with diabetes mellitus, the development of small molecule agonists could have substantial advantages. We previously reported a lead for small molecule GLP1 receptor agonist development representing the pentapeptide NRTFD. In this work, we have prepared an NRTFD derivative incorporating a photolabile benzoylphenylalanine and used it to define its site of action. This peptide probe was a full agonist with potency similar to NRTFD, which bound specifically and saturably to a single, distinct site within the GLP1 receptor. Peptide mapping using cyanogen bromide and endoproteinase Lys-C cleavage of labeled wild type and M397L mutant receptor constructs identified the site of covalent attachment of NRTFD within the third extracellular loop above the sixth transmembrane segment (TM6). This region is the same as that identified using an analogous photolabile probe based on secretin receptor sequences, and has been shown in mutagenesis studies to be important for natural agonist action of several members of this family. While these observations suggest that small molecule ligands can act at a site bordering the third extracellular loop to activate this class B GPCR, the relationship of this site to the site of action of the amino-terminal end of the natural agonist peptide is unclear.