Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors.
Year : 2008
Volume : 51
Issue : 14
First Page : 4315
Last Page : 4320
Authors : Alstermark C, Amin K, Dinn SR, Elebring T, Fjellström O, Fitzpatrick K, Geiss WB, Gottfries J, Guzzo PR, Harding JP, Holmén A, Kothare M, Lehmann A, Mattsson JP, Nilsson K, Sundén G, Swanson M, von Unge S, Woo AM, Wyle MJ, Zheng X.
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.