title: Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors.
abstract: 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.
authors.affiliation: AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Alstermark
authors.forename: Kosrat
authors.initials: K
authors.lastname: Amin
authors.forename: Sean R
authors.initials: SR
authors.lastname: Dinn
authors.forename: Thomas
authors.initials: T
authors.lastname: Elebring
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzpatrick
authors.forename: William B
authors.initials: WB
authors.lastname: Geiss
authors.forename: Johan
authors.initials: J
authors.lastname: Gottfries
authors.forename: Peter R
authors.initials: PR
authors.lastname: Guzzo
authors.forename: James P
authors.initials: JP
authors.lastname: Harding
authors.forename: Anders
authors.initials: A
authors.lastname: Holmén
authors.forename: Mohit
authors.initials: M
authors.lastname: Kothare
authors.forename: Anders
authors.initials: A
authors.lastname: Lehmann
authors.forename: Jan P
authors.initials: JP
authors.lastname: Mattsson
authors.forename: Karolina
authors.initials: K
authors.lastname: Nilsson
authors.forename: Gunnel
authors.initials: G
authors.lastname: Sundén
authors.forename: Marianne
authors.initials: M
authors.lastname: Swanson
authors.forename: Sverker
authors.initials: S
authors.lastname: von Unge
authors.forename: Alex M
authors.initials: AM
authors.lastname: Woo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wyle
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
mesh_terms: 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
chemical_list: D018755:GABA Agonists; D058786:GABA-B Receptor Agonists