Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4

被引：78

作者：

Cheung, Mui ^{[1
]}

Bao, Weike ^{[1
]}

Behm, David J. ^{[1
]}

Brooks, Carl A. ^{[1
]}

Bury, Michael J. ^{[1
]}

Dowdell, Sarah E. ^{[1
]}

Eidam, Hilary S. ^{[1
]}

Fox, Ryan M. ^{[1
]}

Goodman, Krista B. ^{[1
]}

Holt, Dennis A. ^{[1
]}

Lee, Dennis ^{[1
]}

Roethke, Theresa J. ^{[1
]}

Willette, Robert N. ^{[1
]}

Xu, Xiaoping ^{[1
]}

Ye, Guosen ^{[1
]}

Thorneloe, Kevin S. ^{[1
]}

机构：

[1] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, Heart Failure Discovery Performance Unit, King Of Prussia, PA 19406 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 05期

关键词：

GSK2193874; TRPV4; antagonist; inhibitor; congestive heart failure; L-type channel inhibition; TRPV4; ANTAGONISTS; CATION CHANNEL; LUNG INJURY; ION-CHANNEL; IDENTIFICATION; ACTIVATION; INHIBITION; BARRIER; SERIES; EDEMA;

D O I：

10.1021/acsmedchemlett.7b00094

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.

引用

页码：549 / 554

页数：6

共 21 条

[1]

Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier [J].

Alvarez, Diego F. ;

King, Judy A. ;

Weber, David ;

Addison, Emile ;

Liedtke, Wolfgang ;

Townsley, Mary I. .

CIRCULATION RESEARCH, 2006, 99 (09) :988-995

[2]

TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury [J].

Balakrishna, Shrilatha ;

Song, Weifeng ;

Achanta, Satyanarayana ;

Doran, Stephen F. ;

Liu, Boyi ;

Kaelberer, Melanie M. ;

Yu, Zhihong ;

Sui, Aiwei ;

Cheung, Mui ;

Leishman, Emma ;

Eidam, Hilary S. ;

Ye, Guosen ;

Willette, Robert N. ;

Thorneloe, Kevin S. ;

Bradshaw, Heather B. ;

Matalon, Sadis ;

Jordt, Sven-Eric .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2014, 307 (02) :L158-L172

[3]

Brooks C. A., 2011, TRPV4 Antagonists. PCT Int. Appl, Patent No. [PTC/US2011/029570, 2011029570]

[4]

Brooks C. A., 2011, TRPV4 Antagonists. PCT Int. Appl, Patent No. [W011119704, 11119704]

[5]

Brooks C. A., 2011, TRPV4 Antagonists. PCT Int. Appl, Patent No. [W011119693, 11119693]

[6]

Brooks C. A., 2011, TRPV4 Antagonists. PCT Int. Appl, Patent No. [W011119704, US2011/029584, 2011029584]

[7]

Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2 [J].

Delany, NS ;

Hurle, M ;

Facer, P ;

Alnadaf, T ;

Plumpton, C ;

Kinghorn, I ;

See, CG ;

Costigan, M ;

Anand, P ;

Woolf, CJ ;

Crowther, D ;

Sanseau, P ;

Tate, SN .

PHYSIOLOGICAL GENOMICS, 2001, 4 (03) :165-174

[8]

Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis [J].

Everaerts, Wouter ;

Zhen, Xiaoguang ;

Ghosh, Debapriya ;

Vriens, Joris ;

Gevaert, Thomas ;

Gilbert, James P. ;

Hayward, Neil J. ;

McNamara, Colleen R. ;

Xue, Fenqin ;

Moran, Magdalene M. ;

Strassmaier, Timothy ;

Uykal, Eda ;

Owsianik, Grzegorz ;

Vennekens, Rudi ;

De Ridder, Dirk ;

Nilius, Bernd ;

Fanger, Christopher M. ;

Voets, Thomas .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (44) :19084-19089

[9]

The vanilloid transient receptor potential channel TRPV4: From structure to disease [J].

Everaerts, Wouter ;

Nilius, Bernd ;

Owsianik, Grzegorz .

PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, 2010, 103 (01) :2-17

[10]

Güler AD, 2002, J NEUROSCI, V22, P6408

← 1 2 3 →