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

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

Affiliation

  • 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.

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