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Title: Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily

Abstract

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1005968
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 52; Journal Issue: (5) ; 03, 2009; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CARCINOMAS; CLINICAL TRIALS; ENZYMES; IN VIVO; NEOPLASMS; ORAL ADMINISTRATION; PHOSPHOTRANSFERASES; PYRIDINE; SAFETY; SOLUBILITY

Citation Formats

Schroeder, Gretchen M, An, Yongmi, Cai, Zhen-Wei, Chen, Xiao-Tao, Clark, Cheryl, Cornelius, Lyndon A.M., Dai, Jun, Gullo-Brown, Johnni, Gupta, Ashok, Henley, Benjamin, Hunt, John T, Jeyaseelan, Robert, Kamath, Amrita, Kim, Kyoung, Lippy, Jonathan, Lombardo, Louis J, Manne, Veeraswamy, Oppenheimer, Simone, Sack, John S, Schmidt, Robert J, Shen, Guoxiang, Stefanski, Kevin, Tokarski, John S, Trainor, George L, Wautlet, Barri S, Wei, Donna, Williams, David K, Zhang, Yingru, Zhang, Yueping, Fargnoli, Joseph, Borzilleri, Robert M, and BMS). Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily. United States: N. p., 2009. Web. doi:10.1021/jm801586s.
Schroeder, Gretchen M, An, Yongmi, Cai, Zhen-Wei, Chen, Xiao-Tao, Clark, Cheryl, Cornelius, Lyndon A.M., Dai, Jun, Gullo-Brown, Johnni, Gupta, Ashok, Henley, Benjamin, Hunt, John T, Jeyaseelan, Robert, Kamath, Amrita, Kim, Kyoung, Lippy, Jonathan, Lombardo, Louis J, Manne, Veeraswamy, Oppenheimer, Simone, Sack, John S, Schmidt, Robert J, Shen, Guoxiang, Stefanski, Kevin, Tokarski, John S, Trainor, George L, Wautlet, Barri S, Wei, Donna, Williams, David K, Zhang, Yingru, Zhang, Yueping, Fargnoli, Joseph, Borzilleri, Robert M, & BMS). Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily. United States. https://doi.org/10.1021/jm801586s
Schroeder, Gretchen M, An, Yongmi, Cai, Zhen-Wei, Chen, Xiao-Tao, Clark, Cheryl, Cornelius, Lyndon A.M., Dai, Jun, Gullo-Brown, Johnni, Gupta, Ashok, Henley, Benjamin, Hunt, John T, Jeyaseelan, Robert, Kamath, Amrita, Kim, Kyoung, Lippy, Jonathan, Lombardo, Louis J, Manne, Veeraswamy, Oppenheimer, Simone, Sack, John S, Schmidt, Robert J, Shen, Guoxiang, Stefanski, Kevin, Tokarski, John S, Trainor, George L, Wautlet, Barri S, Wei, Donna, Williams, David K, Zhang, Yingru, Zhang, Yueping, Fargnoli, Joseph, Borzilleri, Robert M, and BMS). 2009. "Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily". United States. https://doi.org/10.1021/jm801586s.
@article{osti_1005968,
title = {Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily},
author = {Schroeder, Gretchen M and An, Yongmi and Cai, Zhen-Wei and Chen, Xiao-Tao and Clark, Cheryl and Cornelius, Lyndon A.M. and Dai, Jun and Gullo-Brown, Johnni and Gupta, Ashok and Henley, Benjamin and Hunt, John T and Jeyaseelan, Robert and Kamath, Amrita and Kim, Kyoung and Lippy, Jonathan and Lombardo, Louis J and Manne, Veeraswamy and Oppenheimer, Simone and Sack, John S and Schmidt, Robert J and Shen, Guoxiang and Stefanski, Kevin and Tokarski, John S and Trainor, George L and Wautlet, Barri S and Wei, Donna and Williams, David K and Zhang, Yingru and Zhang, Yueping and Fargnoli, Joseph and Borzilleri, Robert M and BMS)},
abstractNote = {Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.},
doi = {10.1021/jm801586s},
url = {https://www.osti.gov/biblio/1005968}, journal = {J. Med. Chem.},
issn = {0022-2623},
number = (5) ; 03, 2009,
volume = 52,
place = {United States},
year = {Tue Dec 01 00:00:00 EST 2009},
month = {Tue Dec 01 00:00:00 EST 2009}
}