Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors.
We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B 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.
Alstermark
Christer
C
AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden.
Amin
Kosrat
K
Dinn
Sean R
SR
Elebring
Thomas
T
Fjellström
Ola
O
Fitzpatrick
Kevin
K
Geiss
William B
WB
Gottfries
Johan
J
Guzzo
Peter R
PR
Harding
James P
JP
Holmén
Anders
A
Kothare
Mohit
M
Lehmann
Anders
A
Mattsson
Jan P
JP
Nilsson
Karolina
K
Sundén
Gunnel
G
Swanson
Marianne
M
von Unge
Sverker
S
Woo
Alex M
AM
Wyle
Michael J
MJ
Zheng
Xiaozhang
X
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D058786:GABA-B Receptor Agonists; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists