Discovery of Imidazopyridine Derivatives as Highly Potent Respiratory Syncytial Virus Fusion Inhibitors

被引：74

作者：

Feng, Song ^{[1
]}

Hong, Di ^{[1
]}

Wang, Baoxia ^{[1
]}

Zheng, Xiufang ^{[1
]}

Miao, Kun ^{[1
]}

Wang, Lisha ^{[2
]}

Yun, Hongying ^{[1
]}

Gao, Lu ^{[3
]}

Zhao, Shuhai ^{[1
]}

Shen, Hong C. ^{[1
]}

机构：

[1] Roche Innovat Ctr Shanghai, Med Chem, Shanghai 201203, Peoples R China

[2] Roche Innovat Ctr Shanghai, Mol Design & Chem Biol, Shanghai 201203, Peoples R China

[3] Roche Innovat Ctr Shanghai, Infect Dis Pharmaceut Res & Early Dev, Shanghai 201203, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 03期

关键词：

Respiratory syncytial virus (RSV); virus; antiviral; fusion inhibitors; imidazopyridine; heterocycle; OPTIMIZATION; INFLUENZA; ENTRY;

D O I：

10.1021/acsmedchemlett.5b00008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of imidazolepyridine derivatives were designed and synthesized according to the established docking studies. The imidazopyridine derivatives were found to have good potency and physical-chemical properties. Several highly potent compounds such as 8ji, 8j1, and 8jm were identified with single nanomolar activities. The most potent compound 8jrn showed an IC50 of 3 nM, lower nnicrosome clearance and no CYP inhibition. The profile of 8jrn appeared to be superior to BMS433771, and supported further optimization.

引用

页码：359 / 362

页数：4

共 24 条

[1] Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121) [J].

Bonfanti, Jean-Francois ;

Meyer, Christophe ;

Doublet, Frederic ;

Fortin, Jerome ;

Muller, Philippe ;

Queguiner, Laurence ;

Gevers, Tom ;

Janssens, Peggy ;

Szel, Heidi ;

Willebrords, Rudy ;

Timmerman, Philip ;

Wuyts, Koen ;

van Remoortere, Pieter ;

Janssens, Frans ;

Wigerinck, Piet ;

Andries, Koen .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :875-896

[2]

Bonfanti JF, 2009, CURR OPIN DRUG DISC, V12, P479

[3] A Prospective Three-Year Cohort Study of the Epidemiology and Virology of Acute Respiratory Infections of Children in Rural India [J].

Broor, Shobha ;

Parveen, Shama ;

Bharaj, Preeti ;

Prasad, Velisetty S. ;

Srinivasulu, Kavalu N. ;

Sumanth, Krishna M. ;

Kapoor, Suresh Kumar ;

Fowler, Karen ;

Sullender, Wayne M. .

PLOS ONE, 2007, 2 (06)

[4] Antiviral activity and molecular mechanism of an orally active respiratory syncytial virus fusion inhibitor [J].

Cianci, C ;

Meanwell, N ;

Krystal, M .

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2005, 55 (03) :289-292

[5] Targeting a binding pocket within the trimer-of-hairpins: Small-molecule inhibition of viral fusion [J].

Cianci, C ;

Langley, DR ;

Dischino, DD ;

Sun, YX ;

Yu, KL ;

Stanley, A ;

Roach, J ;

Li, ZF ;

Dalterio, R ;

Colonno, R ;

Meanwell, NA ;

Krystal, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (42) :15046-15051

[6] Oral efficacy of a respiratory syncytial virus inhibitor in rodent models of infection [J].

Cianci, C ;

Genovesi, EV ;

Lamb, L ;

Medina, I ;

Yang, Z ;

Zadjura, L ;

Yang, H ;

D'Arienzo, C ;

Sin, N ;

Yu, KL ;

Combrink, K ;

Li, ZF ;

Colonno, R ;

Meanwell, N ;

Clark, J ;

Krystal, M .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (07) :2448-2454

[7] Orally active fusion inhibitor of respiratory syncytial virus [J].

Cianci, C ;

Yu, KL ;

Combrink, K ;

Sin, N ;

Pearce, B ;

Wang, A ;

Civiello, R ;

Voss, S ;

Luo, GX ;

Kadow, K ;

Genovesi, EV ;

Venables, B ;

Gulgeze, H ;

Trehan, A ;

James, J ;

Lamb, L ;

Medina, I ;

Roach, J ;

Yang, Z ;

Zadjura, L ;

Colonno, R ;

Clark, J ;

Meanwell, N ;

Krystal, M .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (02) :413-422

[8] Progress in understanding and controlling respiratory syncytial virus: Still crazy after all these years [J].

Collins, Peter L. ;

Melero, Jose A. .

VIRUS RESEARCH, 2011, 162 (1-2) :80-99

[9] The structural biology of type I viral membrane fusion [J].

Colman, PM ;

Lawrence, MC .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (04) :309-319

[10] Respiratory syncytial virus fusion inhibitors. Part 6: An examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety [J].

Combrink, Keith D. ;

Gulgeze, H. Belgin ;

Thuring, Jan W. ;

Yu, Kuo-Long ;

Civiello, Rita L. ;

Zhang, Yi ;

Pearce, Bradley C. ;

Yin, Zhiwei ;

Langley, David R. ;

Kadow, Kathleen F. ;

Cianci, Christopher W. ;

Li, Zhufang ;

Clarke, Junius ;

Genovesi, Eugene V. ;

Medina, Ivette ;

Lamb, Lucinda ;

Yang, Zheng ;

Zadjura, Lisa ;

Krystal, Mark ;

Meanwell, Nicholas A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (17) :4784-4790

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