Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors

Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors

We have previously demonstrated that the prototypical GABAB receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABAB agonists could be exploited for the treatment of gastroesophageal reflux dis...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 51; no. 14; pp. 4315 - 4320
Main Authors: Alstermark, Christer, Amin, Kosrat, Dinn, Sean R, Elebring, Thomas, Fjellström, Ola, Fitzpatrick, Kevin, Geiss, William B, Gottfries, Johan, Guzzo, Peter R, Harding, James P, Holmén, Anders, Kothare, Mohit, Lehmann, Anders, Mattsson, Jan P, Nilsson, Karolina, Sundén, Gunnel, Swanson, Marianne, von Unge, Sverker, Woo, Alex M, Wyle, Michael J, Zheng, Xiaozhang
Format: Journal Article
Language:English
Published: Washington, DC American Chemical Society 24-07-2008
Subjects:
Animals
Biological and medical sciences
Dose-Response Relationship, Drug
GABA Agonists - chemistry
GABA Agonists - pharmacology
GABA Agonists - therapeutic use
GABA-B Receptor Agonists
Gabaergic and benzodiazepinic system
Gastroesophageal Reflux - drug therapy
Humans
Magnetic Resonance Spectroscopy
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Spectrometry, Mass, Fast Atom Bombardment
Gastroesophageal reflux
Agonist
Rat
Esophageal disease
Rodentia
In vitro
Biological activity
Phosphorus Organic compounds
In vivo
Vertebrata
Mammalia
Mouse
Aminoacid
Animal
Digestive diseases
Inhibitor
Fluorine Organic compounds
R configuration
Gabaergic receptor B
Chemical synthesis
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:We have previously demonstrated that the prototypical GABAB receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABAB agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABAB agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABAB agonists devoid of classical GABAB agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.
Bibliography:Experimental details for synthesis of (R)-3, (S)-7, 8, (S)-8, and the N-benzamide derivatives of (S)-7 and (R)-7; procedure for determination of the optical purity of (S)-7 and (R)-7; description of measurement of [Ca2+]i in a fluorescence imaging plate reader (FLIPR); elemental analysis results of compounds (S)-3, 5, 7, (S)-7, (R)-7, and (S)-8. This material is available free of charge via the Internet at http://pubs.acs.org.
ark:/67375/TPS-XW4VBT19-L
istex:5B7C0D32EAF92C6F732EF5A6D193FEEDF5CA9F89
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701425k