Activation of the G-Protein-Coupled Receptor 119: A Conformation-Based Hypothesis for Understanding Agonist Response

被引：45

作者：

McClure, Kim F. ^{[1
]}

Darout, Etzer ^{[1
]}

Guimaraes, Cristiano R. W. ^{[1
]}

DeNinno, Michael P. ^{[1
]}

Mascitti, Vincent ^{[1
]}

Munchhof, Michael J. ^{[1
]}

Robinson, Ralph P. ^{[1
]}

Kohrt, Jeffrey ^{[1
]}

Harris, Anthony R. ^{[1
]}

Moore, Dianna E. ^{[1
]}

Li, Bryan ^{[1
]}

Samp, Lacey ^{[1
]}

Lefker, Bruce A. ^{[1
]}

Futatsugi, Kentaro ^{[1
]}

Kung, Daniel ^{[1
]}

Bonin, Paul D. ^{[2
]}

Cornelius, Peter ^{[2
]}

Wang, Ruduan ^{[2
]}

Salter, Eben ^{[2
]}

Hornby, Sam ^{[2
]}

Kalgutkar, Amit S. ^{[3
]}

Chen, Yue ^{[3
]}

机构：

[1] Pfizer Global Res & Dev, Dept Med Chem, Groton, CT 06340 USA

[2] Pfizer Global Res & Dev, Dept Discovery Biol, Groton, CT 06340 USA

[3] Pfizer Global Res & Dev, Dept Drug Metab & Pharmaceut Sci, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 06期

关键词：

GPR119; AGONISTS; DISCOVERY; AGENTS; TARGETS; POTENT;

D O I：

10.1021/jm200003p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.

引用

页码：1948 / 1952

页数：5

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