Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

被引：38

作者：

Brand, Stephen ^{[1
]}

Ko, Eun Jung ^{[1
]}

Viayna, Elisabet ^{[1
]}

Thompson, Stephen ^{[1
]}

Spinks, Daniel ^{[1
]}

Thomas, Michael ^{[1
]}

Sandberg, Lars ^{[1
]}

Francisco, Amanda F. ^{[2
]}

Jayawardhana, Shiromani ^{[2
]}

Smith, Victoria C. ^{[1
]}

Jansen, Chimed ^{[1
]}

De Rycker, Manu ^{[1
]}

Thomas, John ^{[1
]}

MacLean, Lorna ^{[1
]}

Osuna-Cabello, Maria ^{[1
]}

Riley, Jennifer ^{[1
]}

Scullion, Paul ^{[1
]}

Stojanovski, Laste ^{[1
]}

Simeons, Frederick R. C. ^{[1
]}

Epemolu, Ola ^{[1
]}

Shishikura, Yoko ^{[1
]}

Crouch, Sabrinia D. ^{[3
]}

Bakshi, Tania S. ^{[4
]}

Nixon, Christopher J. ^{[4
]}

Reid, Iain H. ^{[5
]}

Hill, Alan P. ^{[5
]}

Underwood, Tim Z. ^{[5
]}

Hindley, Sean J. ^{[5
]}

Robinson, Sharon A. ^{[6
]}

Kelly, John M. ^{[2
]}

Fiandor, Jose M. ^{[3
]}

Wyatt, Paul G. ^{[1
]}

Marco, Maria ^{[3
]}

Miles, Timothy J. ^{[3
]}

Read, Kevin D. ^{[1
]}

Gilbert, Ian H. ^{[1
]}

机构：

[1] Univ Dundee, Div Biol Chem & Drug Discovery, Coll Life Sci, Drug Discovery Unit,Sir James Black Ctr, Dundee DD1 5EH, Scotland

[2] London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, Keppel St, London WC1E 7HT, England

[3] GlaxoSmithKline, Dis Developing World, Calle Severo Ochoa 2, Madrid 28760, Spain

[4] GlaxoSmithKline, 1250 South Collegeville Rd,POB 5089, Collegeville, PA 19426 USA

[5] GlaxoSmithKline, Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[6] GlaxoSmithKline, David Jack Ctr R&D, Pk Rd, Ware SG12 0DP, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 17期

基金：

英国惠康基金;

关键词：

CHAGAS-DISEASE; DRUG DISCOVERY; LIGAND EFFICIENCY; RANDOMIZED-TRIAL; IDENTIFICATION; BENZNIDAZOLE; POSACONAZOLE; SELECTION;

D O I：

10.1021/acs.jmedchem.7b00463

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

引用

页码：7284 / 7299

页数：16

共 65 条

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