Literature DB >> 25313322

Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

Stefan Peukert1, Richard Hughes1, Jill Nunez1, Guo He1, Zhao Yan1, Rishi Jain1, Luis Llamas1, Sarah Luchansky1, Adam Carlson1, Guiqing Liang1, Vidya Kunjathoor1, Mike Pietropaolo1, Jeffrey Shapiro1, Anja Castellana1, Xiaoping Wu1, Avirup Bose1.   

Abstract

The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.

Entities:  

Keywords:  GLP-1 secretion; GPR39 agonists; GPR39 receptor; Zn2+-sensing receptor; antidiabetic treatment; insulin secretion; β-cell protection

Year:  2014        PMID： 25313322      PMCID： PMC4190643          DOI： 10.1021/ml500240d

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  19 in total

1.  Ligand efficiency: a useful metric for lead selection.

Authors:  Andrew L Hopkins; Colin R Groom; Alexander Alex
Journal:  Drug Discov Today       Date:  2004-05-15       Impact factor: 7.851

2.  The constitutively active orphan G-protein-coupled receptor GPR39 protects from cell death by increasing secretion of pigment epithelium-derived growth factor.

Authors:  Sonja Dittmer; Mert Sahin; Anna Pantlen; Ambrish Saxena; Diamandis Toutzaris; Ana-Luisa Pina; Andreas Geerts; Stefan Golz; Axel Methner
Journal:  J Biol Chem       Date:  2008-01-07       Impact factor: 5.157

3.  Disruption of G protein-coupled receptor 39 impairs insulin secretion in vivo.

Authors:  Frédéric Tremblay; Ann-Marie T Richard; Sarah Will; Jameel Syed; Nancy Stedman; Mylène Perreault; Ruth E Gimeno
Journal:  Endocrinology       Date:  2009-02-12       Impact factor: 4.736

4.  A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats.

Authors:  Atul Sureshrao Akarte; B P Srinivasan; Sonia Gandhi
Journal:  Biochem Pharmacol       Date:  2011-10-12       Impact factor: 5.858

5.  Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39.

Authors:  Frederic Bassilana; Adam Carlson; Jennifer A DaSilva; Bianka Grosshans; Solange Vidal; Valerie Beck; Barbara Wilmeringwetter; Luis A Llamas; Todd B Showalter; Pascal Rigollier; Aaron Bourret; Arun Ramamurthy; Xu Wu; Fred Harbinski; Samantha Plonsky; Lac Lee; Heinz Ruffner; Paola Grandi; Markus Schirle; Jeremy Jenkins; Andreas W Sailer; Tewis Bouwmeester; Jeffrey A Porter; Vic Myer; Peter M Finan; John A Tallarico; Joseph F Kelleher; Klaus Seuwen; Rishi K Jain; Sarah J Luchansky
Journal:  Nat Chem Biol       Date:  2014-03-16       Impact factor: 15.040

6.  Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse.

Authors:  Dieder Moechars; Inge Depoortere; Benoit Moreaux; Betty de Smet; Ilse Goris; Luc Hoskens; Guy Daneels; Stefan Kass; Luc Ver Donck; Theo Peeters; Bernard Coulie
Journal:  Gastroenterology       Date:  2006-10       Impact factor: 22.682

7.  GPR39 signaling is stimulated by zinc ions but not by obestatin.

Authors:  Birgitte Holst; Kristoffer L Egerod; Enrico Schild; Steve P Vickers; Sharon Cheetham; Lars-Ole Gerlach; Laura Storjohann; Carsten E Stidsen; Rob Jones; Annette G Beck-Sickinger; Thue W Schwartz
Journal:  Endocrinology       Date:  2006-09-07       Impact factor: 4.736

8.  Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors.

Authors:  K K McKee; C P Tan; O C Palyha; J Liu; S D Feighner; D L Hreniuk; R G Smith; A D Howard; L H Van der Ploeg
Journal:  Genomics       Date:  1997-12-15       Impact factor: 5.736

9.  GPR39, a receptor of the ghrelin receptor family, plays a role in the regulation of glucose homeostasis in a mouse model of early onset diet-induced obesity.

Authors:  P J Verhulst; A Lintermans; S Janssen; D Loeckx; U Himmelreich; J Buyse; J Tack; I Depoortere
Journal:  J Neuroendocrinol       Date:  2011-06       Impact factor: 3.627

10.  Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells.

Authors:  Arnaud Merglen; Sten Theander; Blanca Rubi; Gaelle Chaffard; Claes B Wollheim; Pierre Maechler
Journal:  Endocrinology       Date:  2003-10-30       Impact factor: 4.736
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  10 in total

1.  Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc.

Authors:  Seiji Sato; Xi-Ping Huang; Wesley K Kroeze; Bryan L Roth
Journal:  Mol Pharmacol       Date:  2016-10-17       Impact factor: 4.436

2.  Orphans to the rescue: orphan G-protein coupled receptors as new antidepressant targets.

Authors:  Paul R Albert
Journal:  J Psychiatry Neurosci       Date:  2020-09-01       Impact factor: 6.186

3.  Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice.

Authors:  Verginia C Cuzon Carlson; Matthew M Ford; Timothy L Carlson; Alejandro Lomniczi; Kathleen A Grant; Betsy Ferguson; Rita P Cervera-Juanes
Journal:  Neuropsychopharmacology       Date:  2019-01-05       Impact factor: 7.853

4.  Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy-The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene.

Authors:  Urszula Doboszewska; Jan Sawicki; Adam Sajnóg; Aleksandra Szopa; Anna Serefko; Katarzyna Socała; Mateusz Pieróg; Dorota Nieoczym; Katarzyna Mlyniec; Gabriel Nowak; Danuta Barałkiewicz; Ireneusz Sowa; Piotr Wlaź
Journal:  Cells       Date:  2022-06-21       Impact factor: 7.666

Review 5.  Leveraging the Gut to Treat Metabolic Disease.

Authors:  Ruth E Gimeno; Daniel A Briere; Randy J Seeley
Journal:  Cell Metab       Date:  2020-03-17       Impact factor: 27.287

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

Authors:  Ola Fjellström; Niklas Larsson; Shin-Ichiro Yasuda; Takuma Tsuchida; Takahiro Oguma; Anna Marley; Charlotte Wennberg-Huldt; Daniel Hovdal; Hajime Fukuda; Yukimi Yoneyama; Kazuyo Sasaki; Anders Johansson; Sara Lundqvist; Johan Brengdahl; Richard J Isaacs; Daniel Brown; Stefan Geschwindner; Lambertus Benthem; Claire Priest; Andrew Turnbull
Journal:  PLoS One       Date:  2015-12-31       Impact factor: 3.240

Review 7.  The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target.

Authors:  Anna Laitakari; Lingzhi Liu; Thomas M Frimurer; Birgitte Holst
Journal:  Int J Mol Sci       Date:  2021-04-08       Impact factor: 5.923

8.  Activation of the zinc-sensing receptor GPR39 promotes T-cell reconstitution after hematopoietic cell transplant in mice.

Authors:  Lorenzo Iovino; Kirsten Cooper; Paul deRoos; Sinéad Kinsella; Cindy Evandy; Tamas Ugrai; Francesco Mazziotta; Kathleen S Ensbey; David Granadier; Kayla Hopwo; Colton Smith; Alex Gagnon; Sara Galimberti; Mario Petrini; Geoffrey R Hill; Jarrod A Dudakov
Journal:  Blood       Date:  2022-06-23       Impact factor: 25.476

Review 9.  Pharmacology and physiology of gastrointestinal enteroendocrine cells.

Authors:  O J Mace; B Tehan; F Marshall
Journal:  Pharmacol Res Perspect       Date:  2015-07-07

Review 10.  Role of GPR39 in Neurovascular Homeostasis and Disease.

Authors:  Yifan Xu; Anthony P Barnes; Nabil J Alkayed
Journal:  Int J Mol Sci       Date:  2021-07-30       Impact factor: 5.923
  10 in total

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