Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal-Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer

被引：121

作者：

Jia, Hong ^{[1
]}

Dai, Guangxiu ^{[1
]}

Weng, Jianyang ^{[1
]}

Zhang, Zhulin ^{[1
]}

Wang, Qing ^{[1
]}

Zhou, Feng ^{[1
]}

Jiao, Longxian ^{[1
]}

Cui, Yumin ^{[1
]}

Ren, Yongxin ^{[1
]}

Fan, Shiming ^{[1
]}

Zhou, Jinghong ^{[1
]}

Qing, Weiguo ^{[1
]}

Gu, Yi ^{[1
]}

Wang, Jian ^{[1
]}

Sai, Yang ^{[1
]}

Su, Weiguo ^{[1
]}

机构：

[1] Hutchison MediPharma Ltd, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 18期

关键词：

HEPATOCYTE GROWTH-FACTOR; RECEPTOR; IDENTIFICATION; EXPRESSION; OPTIMIZATION; CANDIDATE;

D O I：

10.1021/jm500510f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

引用

页码：7577 / 7589

页数：13

共 22 条

[1] Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase [J].

Albrecht, Brian K. ;

Harmange, Jean-Christophe ;

Bauer, David ;

Berry, Loren ;

Bode, Christiane ;

Boezio, Alessandro A. ;

Chen, April ;

Choquette, Deborah ;

Dussault, Isabelle ;

Fridrich, Cary ;

Hirai, Satoko ;

Hoffman, Doug ;

Larrow, Jay F. ;

Kaplan-Lefko, Paula ;

Lin, Jasmine ;

Lohman, Julia ;

Long, Alexander M. ;

Moriguchi, Jodi ;

O'Connor, Anne ;

Potashman, Michele H. ;

Reese, Monica ;

Rex, Karen ;

Siegmund, Aaron ;

Shah, Kavita ;

Shimanovich, Roman ;

Springer, Stephanie K. ;

Teffera, Yohannes ;

Yang, Yajing ;

Zhang, Yihong ;

Bellon, Steven F. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (10) :2879-2882

[2] IDENTIFICATION OF THE HEPATOCYTE GROWTH-FACTOR RECEPTOR AS THE C-MET PROTOONCOGENE PRODUCT [J].

BOTTARO, DP ;

RUBIN, JS ;

FALETTO, DL ;

CHAN, AML ;

KMIECIK, TE ;

VANDEWOUDE, GF ;

AARONSON, SA .

SCIENCE, 1991, 251 (4995) :802-804

[3] SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo [J].

Buchanan, Sean G. ;

Hendle, Jorg ;

Lee, Patrick S. ;

Smith, Christopher R. ;

Bounaud, Pierre-Yves ;

Jessen, Katti A. ;

Tang, Crystal M. ;

Huser, Nanni H. ;

Felce, Jeremy D. ;

Froning, Karen J. ;

Peterman, Marshall C. ;

Aubol, Brandon E. ;

Gessert, Steve F. ;

Sauder, Michael ;

Schwinn, Kenneth D. ;

Russell, Marijane ;

Rooney, Isabelle A. ;

Adams, Jason ;

Leon, Barbara C. ;

Do, Tuan H. ;

Blaney, Jeff M. ;

Sprengeler, Paul A. ;

Thompson, Devon A. ;

Smyth, Lydia ;

Pelletier, Laura A. ;

Atwell, Shane ;

Holme, Kevin ;

Wasserman, Stephen R. ;

Emtage, Spencer ;

Burley, Stephen K. ;

Reich, Siegfried H. .

MOLECULAR CANCER THERAPEUTICS, 2009, 8 (12) :3181-3190

[4] Lessons from (S)-6-(1-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an Inhibitor of Receptor Tyrosine Kinase c-Met with High Protein Kinase Selectivity but Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats [J].

Cui, J. Jean ;

Shen, Hong ;

Tran-Dube, Michelle ;

Nambu, Mitchell ;

McTigue, Michele ;

Grodsky, Neil ;

Ryan, Kevin ;

Yamazaki, Shinji ;

Aguirre, Shirley ;

Parker, Max ;

Li, Qiuhua ;

Zou, Helen ;

Christensen, James .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (17) :6651-6665

[5] Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2-(4-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the Treatment of Cancer [J].

Cui, J. Jean ;

McTigue, Michele ;

Nambu, Mitchell ;

Tran-Dube, Michelle ;

Pairish, Mason ;

Shen, Hong ;

Jia, Lei ;

Cheng, Hengmiao ;

Hoffman, Jacqui ;

Le, Phuong ;

Jalaie, Mehran ;

Goetz, Gilles H. ;

Ryan, Kevin ;

Grodsky, Neil ;

Deng, Ya-Li ;

Parker, Max ;

Timofeevski, Sergei ;

Murray, Brion W. ;

Yamazaki, Shinji ;

Aguirre, Shirley ;

Li, Qiuhua ;

Zou, Helen ;

Christensen, James .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (18) :8091-8109

[6]

D'Cruz C., 2014, AM ASS CANC RES AACR

[7] Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications [J].

Diamond, Sharon ;

Boer, Jason ;

Maduskuie, Thomas P., Jr. ;

Falahatpisheh, Nikoo ;

Li, Yu ;

Yeleswaram, Swamy .

DRUG METABOLISM AND DISPOSITION, 2010, 38 (08) :1277-1285

[8]

DIRENZO MF, 1991, ONCOGENE, V6, P1997

[9]

Gavine P.R., 2013, CANC RES S, DOI [10.1158/1538-7445, DOI 10.1158/1538-7445]

[10] Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor. [J].

Gu, Yi ;

Sai, Yang ;

Wang, Jian ;

Xia, Sumei ;

Wang, Guanglin ;

Zhao, Yuansheng ;

Zhang, Li ;

Yang, Wenqing ;

Dai, Guangxiu ;

Zhang, Weihan ;

Gong, Qisun ;

Tian, Zhenping ;

Su, Weiguo .

CANCER RESEARCH, 2013, 73 (08)

← 1 2 3 →