Format

Send to

Choose Destination
PLoS One. 2015 Dec 31;10(12):e0145849. doi: 10.1371/journal.pone.0145849. eCollection 2015.

Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.

Author information

1
Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
2
Discovery Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
3
Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
4
Discovery Sciences, AstraZeneca R&D, Mereside, United Kingdom.
5
Bioscience CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
6
DMPK CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
7
DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
8
Molecular Sensing, Inc., Nashville, Tennessee, United States of America.
9
CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

Abstract

Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

PMID:
26720709
PMCID:
PMC4697807
DOI:
10.1371/journal.pone.0145849
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center