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

被引：40

作者：

Alstermark, Christer ^{[1
]}

Amin, Kosrat ^{[1
]}

Dinn, Sean R. ^{[2
]}

Elebring, Thomas ^{[1
]}

Fjellstroem, Ola ^{[1
]}

Fitzpatrick, Kevin ^{[2
]}

Geiss, William B. ^{[2
]}

Gottfries, Johan ^{[1
]}

Guzzo, Peter R. ^{[2
]}

Harding, James P. ^{[2
]}

Holmen, Anders ^{[1
]}

Kothare, Mohit ^{[2
]}

Lehmann, Anders ^{[1
]}

Mattsson, P. ^{[1
]}

Nilsson, Karolina ^{[1
]}

Sunden, Gunnel ^{[1
]}

Swanson, Marianne ^{[1
]}

von Unge, Sverker ^{[1
]}

Woo, Alex M. ^{[2
]}

Wyle, Michael J. ^{[2
]}

Zheng, Xiaozhang ^{[2
]}

机构：

[1] AstraZeneca R&D, S-43183 Molndal, Sweden

[2] Albany Mol Res Inc, Albany, NY 12212 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 14期

关键词：

D O I：

10.1021/jm701425k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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, GABAB agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABAB agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABAB agonists devoid of classical GABAB 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.

引用

页码：4315 / 4320

页数：6

共 22 条

[1]

AMIN K, 1999, Patent No. 041743

[2] 1,1-Diethoxyethylphosphinates and phosphonites. Intermediates for the synthesis of functional phosphorus acids [J].