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Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABA_B) Receptor Agonists as Gastroesophageal Reflux Inhibitors

Supporting Info

Christer Alstermark^†, Kosrat Amin^†, Sean R. Dinn^‡, Thomas Elebring*^†, Ola Fjellstr

m^†, Kevin Fitzpatrick^‡, William B. Geiss^‡, Johan Gottfries^†, Peter R. Guzzo^‡, James P. Harding^‡, Anders Holm

n^†, Mohit Kothare^‡, Anders Lehmann^†, Jan P. Mattsson^†, Karolina Nilsson^†, Gunnel Sund

n^†, Marianne Swanson^†, Sverker von Unge^†, Alex M. Woo^‡, Michael J. Wyle^‡ and Xiaozhang Zheng^‡

AstraZeneca R&D M

lndal, S-431 83 M

lndal, Sweden, and Albany Molecular Research, Inc., 21 Corporate Circle, P.O. Box 15098, Albany, New York 12212-5098

J. Med. Chem., 2008, 51 (14), pp 4315–4320

DOI: 10.1021/jm701425k

Publication Date (Web): June 25, 2008

†

AstraZeneca R&D Mlndal.

‡

Albany Molecular Research, Inc.

* To whom correspondence should be addressed. Phone: (+46) 31 7762116. Fax: (+46) 31 7763724. E-mail: Thomas.Elebring@astrazeneca.com.

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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History

Published In Issue July 24, 2008
Article ASAPJune 25, 2008
Received: November 12, 2007

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Article

Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABA_B) Receptor Agonists as Gastroesophageal Reflux Inhibitors