Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile

被引：6

作者：

Blanco, Maria-Jesus ^{[1
]}

Vetman, Tatiana ^{[1
]}

Chandrasekhar, Srinivasan ^{[1
]}

Fisher, Matthew J. ^{[1
]}

Harvey, Anita ^{[1
]}

Chambers, Mark ^{[1
]}

Lin, Chaohua ^{[1
]}

Mudra, Daniel ^{[1
]}

Oskins, Jennifer ^{[1
]}

Wang, Xu-Shan ^{[1
]}

Yu, Xiao-Peng ^{[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 / 03期

关键词：

EP4 receptor antagonist; Structure-activity relationship (SAR); Prostaglandin E2; Human whole blood (hWB) assay; Inflammation; Pain; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CYCLO-OXYGENASE-2; INHIBITORS; OSTEOARTHRITIS; RISK; PAIN;

D O I：

10.1016/j.bmcl.2015.12.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood ( hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：931 / 935

页数：5

共 17 条

[1] Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain [J].

Benschop, R. J. ;

Collins, E. C. ;

Darling, R. J. ;

Allan, B. W. ;

Leung, D. ;

Conner, E. M. ;

Nelson, J. ;

Gaynor, B. ;

Xu, J. ;

Wang, X-F ;

Lynch, R. A. ;

Li, B. ;

McCarty, D. ;

Oskins, J. L. ;

Lin, C. ;

Johnson, K. W. ;

Chambers, M. G. .

OSTEOARTHRITIS AND CARTILAGE, 2014, 22 (04) :578-585

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

Blanco, Maria-Jesus ;

Vetman, Tatiana ;

Chandrasekhar, Srinivasan ;

Fisher, Matthew J. ;

Harvey, Anita ;

Mudra, Daniel ;

Wang, Xu-Shan ;

Yu, Xiao-Peng ;

Schiffler, Matthew A. ;

Warshawsky, Alan M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (01) :105-109

[3]

Blanco-Pillado M.-J., [No title captured], Patent No. [WO2015094912, 2015094912]

[4]

Borriello M, 2013, PHARM PAT ANAL, V2, P387, DOI [10.4155/ppa.13.15, 10.4155/PPA.13.15]

[5] Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor [J].

Burch, Jason D. ;

Farand, Julie ;

Colucci, John ;

Sturino, Claudio ;

Ducharme, Yves ;

Friesen, Richard W. ;

Levesque, Jean-Francois ;

Gagne, Sebastien ;

Wrona, Mark ;

Therien, Alex G. ;

Mathieu, Marie-Claude ;

Denis, Danielle ;

Vigneault, Erika ;

Xu, Daigen ;

Clark, Patsy ;

Rowland, Steve ;

Han, Yongxin .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (03) :1041-1046

[6] The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? [J].

Combe, R ;

Bramwell, S ;

Field, MJ .

NEUROSCIENCE LETTERS, 2004, 370 (2-3) :236-240

[7] General and Scalable Amide Bond Formation with Epimerization-Prone Substrates Using T3P and Pyridine [J].

Dunetz, Joshua R. ;

Xiang, Yanqiao ;

Baldwin, Aaron ;

Ringling, Justin .

ORGANIC LETTERS, 2011, 13 (19) :5048-5051

[8] The many roles for fluorine in medicinal chemistry [J].

Hagmann, William K. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (15) :4359-4369

[9]

Hardman L. G., 2001, GOODMANS PHARM BASIS

[10] Utility of animal models for identification of potential therapeutics for rheumatoid arthritis [J].

Hegen, M. ;

Keith, J. C., Jr. ;

Collins, M. ;

Nickerson-Nutter, C. L. .

ANNALS OF THE RHEUMATIC DISEASES, 2008, 67 (11) :1505-1515

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