Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors

  • J Med Chem. 2008 Jul 24;51(14):4315-20. doi: 10.1021/jm701425k.
Christer Alstermark  1 ,  Kosrat Amin ,  Sean R Dinn ,  Thomas Elebring ,  Ola Fjellström ,  Kevin Fitzpatrick ,  William B Geiss ,  Johan Gottfries ,  Peter R Guzzo ,  James P Harding ,  Anders Holmén ,  Mohit Kothare ,  Anders Lehmann ,  Jan P Mattsson ,  Karolina Nilsson ,  Gunnel Sundén ,  Marianne Swanson ,  Sverker von Unge ,  Alex M Woo ,  Michael J Wyle ,  Xiaozhang Zheng
Affiliations
  • 1. AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden.
PMID: 18578471 DOI: 10.1021/jm701425k
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.