Discovery of 2-Arylbenzoxazoles as Upregulators of Utrophin Production for the Treatment of Duchenne Muscular Dystrophy

被引：67

作者：

Chancellor, Daniel R. ^{[1
]}

Davies, Kay E. ^{[2
]}

De Moor, Olivier ^{[1
]}

Dorgan, Colin R. ^{[1
]}

Johnson, Peter D. ^{[1
]}

Lambert, Adam G. ^{[1
]}

Lawrence, Daniel ^{[1
]}

Lecci, Cristina ^{[1
]}

Maillol, Carole ^{[1
]}

Middleton, Penny J. ^{[1
]}

Nugent, Gary ^{[1
]}

Poignant, Severine D. ^{[1
]}

Potter, Allyson C. ^{[2
]}

Price, Paul D. ^{[1
]}

Pye, Richard J. ^{[1
]}

Storer, Richard ^{[1
]}

Tinsley, Jonathon M. ^{[1
]}

van Well, Renate ^{[1
]}

Vickers, Richard ^{[1
]}

Vile, Julia ^{[1
]}

Wilkes, Fraser J. ^{[1
]}

Wilson, Francis X. ^{[1
]}

Wren, Stephen P. ^{[1
]}

Wynne, Graham M. ^{[1
]}

机构：

[1] Summit Plc, Abingdon OX14 4RY, Oxon, England

[2] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 09期

基金：

英国医学研究理事会;

关键词：

BENZOXAZOLES; INHIBITORS; REPLACEMENT; LUCIFERASE; EXPRESSION; PTC124; GENE;

D O I：

10.1021/jm200135z

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：

A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.

引用

收藏

页码：3241 / 3250

页数：10

相关论文

共 28 条

[1]

Characterization of chemical libraries for luciferase inhibitory activity [J].

Auld, Douglas S. ;

Southall, Noel T. ;

Jadhav, Ajit ;

Johnson, Ronald L. ;

Diller, David J. ;

Simeonov, Anton ;

Austin, Christopher P. ;

Inglese, James .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (08) :2372-2386

[2]

Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124 [J].

Auld, Douglas S. ;

Lovell, Scott ;

Thorne, Natasha ;

Lea, Wendy A. ;

Maloney, David J. ;

Shen, Min ;

Rai, Ganesha ;

Battaile, Kevin P. ;

Thomas, Craig J. ;

Simeonov, Anton ;

Hanzlik, Robert P. ;

Inglese, James .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (11) :4878-4883

[3]

Utrophin: A structural and functional comparison to dystrophin [J].

Blake, DJ ;

Tinsley, JM ;

Davies, KE .

BRAIN PATHOLOGY, 1996, 6 (01) :37-47

[4]

Iron-catalyzed intramolecular O-arylation:: Synthesis of 2-aryl benzoxazoles [J].

Bonnamour, Julien ;

Bolm, Carsten .

ORGANIC LETTERS, 2008, 10 (13) :2665-2667

[5]

Synthesis of 2-arylbenzoxazoles via DDQ promoted oxidative cyclization of phenolic Schiff bases - a solution-phase strategy for library synthesis [J].

Chang, JB ;

Zhao, K ;

Pan, SF .

TETRAHEDRON LETTERS, 2002, 43 (06) :951-954

[6]

New therapies for Duchenne muscular dystrophy: challenges, prospects and clinical trials [J].

Cossu, Giulio ;

Sampaolesi, Maurilio .

TRENDS IN MOLECULAR MEDICINE, 2007, 13 (12) :520-526

[7]

The para-toluenesulfonic acid-promoted synthesis of 2-substituted benzoxazoles and benzimidazoles from diacylated precursors. [J].

DeLuca, MR ;

Kerwin, SM .

TETRAHEDRON, 1997, 53 (02) :457-464

[8]

2-Arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors: Optimization via array synthesis [J].

Harikrishnan, Lalgudi S. ;

Kamau, Muthoni G. ;

Herpin, Timothy F. ;

Morton, George C. ;

Liu, Yalei ;

Cooper, Christopher B. ;

Salvati, Mark E. ;

Qiao, Jennifer X. ;

Wang, Tammy C. ;

Adam, Leonard P. ;

Taylor, David S. ;

Chen, Alice Ye A. ;

Yin, Xiaohong ;

Seethala, Ramakrishna ;

Peterson, Tara L. ;

Nirschl, David S. ;

Miller, Arthur V. ;

Weigelt, Carolyn A. ;

Appiah, Kingsley K. ;

O'Connell, Jonathan C. ;

Lawrence, R. Michael .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (08) :2640-2644

[9]

Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers [J].

Hirawat, Samit ;

Welch, Ellen M. ;

Elfring, Gary L. ;

Northcutt, Valerie J. ;

Paushkin, Sergey ;

Hwang, Seongwoo ;

Leonard, Eileen M. ;

Almstead, Neil G. ;

Ju, William ;

Peltz, Stuart W. ;

Miller, Langdon L. .

JOURNAL OF CLINICAL PHARMACOLOGY, 2007, 47 (04) :430-444

[10]

Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors [J].

Johnson, Steven M. ;

Connelly, Stephen ;

Wilson, Ian A. ;

Kelly, Jeffery W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (02) :260-270