title: Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.
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.
authors.affiliation: Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
authors.affiliation: Discovery Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Larsson
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Tsuchida
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oguma
authors.affiliation: Discovery Sciences, AstraZeneca R&D, Mereside, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Marley
authors.affiliation: Bioscience CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wennberg-Huldt
authors.affiliation: DMPK CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hovdal
authors.affiliation: DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Fukuda
authors.affiliation: DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Yoneyama
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Kawagishi, Toda-shi, Saitama, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Medicinal Chemistry CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Johansson
authors.affiliation: Discovery Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Lundqvist
authors.affiliation: Discovery Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Brengdahl
authors.affiliation: Molecular Sensing, Inc., Nashville, Tennessee, United States of America.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Isaacs
authors.affiliation: Molecular Sensing, Inc., Nashville, Tennessee, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brown
authors.affiliation: Discovery Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.affiliation: Bioscience CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Benthem
authors.affiliation: Discovery Sciences, AstraZeneca R&D, Mereside, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Priest
authors.affiliation: CVMD iMed, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Andrew
authors.initials: A
authors.lastname: Turnbull
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D057166:High-Throughput Screening Assays; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D054852:Small Molecule Libraries; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C495797:GPR39 protein, human; C512928:GPR39 protein, mouse; C535178:GPR39 protein, rat; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D015032:Zinc