Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists

被引：4

作者：

Blanco, Maria-Jesus ^{[1
]}

Vetman, Tatiana ^{[1
]}

Chandrasekhar, Srinivasan ^{[1
]}

Fisher, Matthew J. ^{[1
]}

Harvey, Anita ^{[1
]}

Mudra, Daniel ^{[1
]}

Wang, Xu-Shan ^{[1
]}

Yu, Xiao-Peng ^{[1
]}

Schiffler, Matthew A. ^{[1
]}

Warshawsky, Alan M. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 01期

关键词：

Arthritis pain; EP4 receptor antagonist; Prostaglandin E2; Human whole blood assay; INFLAMMATION; CJ-023,423; ARTHRITIS; RECEPTOR; CONSEQUENCES; DESTRUCTION; INHIBITORS; COX-2;

D O I：

10.1016/j.bmcl.2015.11.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：105 / 109

页数：5

共 12 条

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Blanco, Maria-Jesus
Vetman, Tatiana
Chandrasekhar, Srinivasan
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Mudra, Daniel
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Wang, Xu-Shan
Yu, Xiao-Peng
Warshawsky, Alan M.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (03) : 931 - 935
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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (03) : 1041 - 1046
[3] Discovery of potent and selective EP4 receptor antagonists for treating inflammatory pain
Han, Yongxin
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238
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Blanco, Maria-Jesus
Vetman, Tatiana
Chandrasekhar, Srinivasan
Fisher, Matthew J.
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Chambers, Mark
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Mudra, Daniel
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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (09) : 2303 - 2307
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[6] The Discovery of 4-{1-[({2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic Acid (MK-2894), A Potent and Selective Prostaglandin E2 Subtype 4 Receptor Antagonist
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JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (05) : 2227 - 2238
[7] Discovery of 4-{1-[({1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]cyclopropyl}benzoicacid (MF-766), a highly potent and selective EP4 antagonist for treating inflammatory pain
Colucci, John
Boyd, Michael
Berthelette, Carl
Chiasson, Jean-Francois
Wang, Zhaoyin
Ducharme, Yves
Friesen, Rick
Wrona, Mark
Levesque, Jean-Francois
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Clarke, Patsy
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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (12) : 3760 - 3763
[8] Discovery of novel non-carboxylic acid 5-amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists
Sidduri, Achyutharao
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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (18) : 4450 - 4454
[9] Biphenylsulfonamide endothelin receptor antagonists.: 4.: Discovery of N-[[2′-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ETA selective antagonist
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JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (01) : 125 - 137
[10] Piperazine-based CCR5 antagonists as HIV-1 inhibitors.: IV.: Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-{2-methoxy-1(R)-4-(trifluoromethyl)-phenyl}ethyl-3(S)-methyl-1-piperazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist
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