2008•Journal of Medicinal ChemistryOpen access
Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors
Christer Alstermark, Kosrat Amin, Sean R. Dinn, Thomas Elebring, Ola Fjellström, Kevin Fitzpatrick, William Geiss, Johan Gottfries, Peter R. Guzzo, J. P. Harding, Anders Holmén, M Kothare, Anders Lehmann, Jan P. Mattsson, Karolina Nilsson, Gunnel Sundén, Marianne Swanson, Sverker von Unge, Alex M. Woo, Michael J. Wyle, Xiaozhang Zheng
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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.