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

共 18 条

[1] Protein-based virtual screening of chemical databases. II. Are homology models of G-protein coupled receptors suitable targets? [J].

Bissantz, C ;

Bernard, P ;

Hibert, M ;

Rognan, D .

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2003, 50 (01) :5-25

[2] Novel Pyridylmethylamines as Highly Selective 5-HT1A Superagonists [J].

Bollinger, Stefan ;

Huebner, Harald ;

Heinenmann, Frank W. ;

Meyer, Karsten ;

Gmeiner, Peter .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (19) :7167-7179

[3] A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release [J].

Chu, Zhi-Liang ;

Carroll, Chris ;

Alfonso, Jean ;

Gutierrez, Veronica ;

He, Hongmei ;

Lucman, Annette ;

Pedraza, Melinda ;

Mondala, Helen ;

Gao, Hui ;

Bagnol, Didier ;

Chen, Ruoping ;

Jones, Robert M. ;

Behan, Dominic P. ;

Leonard, James .

ENDOCRINOLOGY, 2008, 149 (05) :2038-2047

[4] N-Oleoyldopamine Enhances Glucose Homeostasis through the Activation of GPR119 [J].

Chu, Zhi-Liang ;

Carroll, Chris ;

Chen, Ruoping ;

Alfonso, Jean ;

Gutierrez, Veronica ;

He, Hongmei ;

Lucman, Annette ;

Xing, Charles ;

Sebring, Kristen ;

Zhou, Jinyao ;

Wagner, Brandee ;

Unett, David ;

Jones, Robert M. ;

Behan, Dominic P. ;

Leonard, James .

MOLECULAR ENDOCRINOLOGY, 2010, 24 (01) :161-170

[5] The synthesis of azabicyclic heterocycles [J].

Darout, Etzer ;

Basak, Arindrajit .

TETRAHEDRON LETTERS, 2010, 51 (22) :2998-3001

[6] Fatty acid amide signaling molecules [J].

Ezzili, Cyrine ;

Otrubova, Katerina ;

Boger, Dale L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (20) :5959-5968

[7] New Nonpeptide-Binding GPCRs as Targets for Diabetes and the Metabolic Syndrome [J].

Fyfe, Matthew C. T. ;

Overton, Hilary A. ;

Procter, Martin J. ;

Reynet, Christine ;

White, Jonathan R. .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 42, 2007, 42 :129-145

[8] GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity [J].

Fyfe, Matthew C. T. ;

McCormack, James G. ;

Overton, Hilary A. ;

Procter, Martin J. ;

Reynet, Christine .

EXPERT OPINION ON DRUG DISCOVERY, 2008, 3 (04) :403-413

[9]

Jones R. M., 2007, [No title captured], Patent No. [WO 2007035355, 2007035355]

[10] The Emergence of GPR119 Agonists as Anti-Diabetic Agents [J].

Jones, Robert M. ;

Leonard, James N. .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 44, 2009, 44 :149-170

← 1 2 →