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

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 si...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-09, Vol.60 (17), p.7284-7299
Main Authors: Brand, Stephen, Ko, Eun Jung, Viayna, Elisabet, Thompson, Stephen, Spinks, Daniel, Thomas, Michael, Sandberg, Lars, Francisco, Amanda F, Jayawardhana, Shiromani, Smith, Victoria C, Jansen, Chimed, De Rycker, Manu, Thomas, John, MacLean, Lorna, Osuna-Cabello, Maria, Riley, Jennifer, Scullion, Paul, Stojanovski, Laste, Simeons, Frederick R. C, Epemolu, Ola, Shishikura, Yoko, Crouch, Sabrinia D, Bakshi, Tania S, Nixon, Christopher J, Reid, Iain H, Hill, Alan P, Underwood, Tim Z, Hindley, Sean J, Robinson, Sharon A, Kelly, John M, Fiandor, Jose M, Wyatt, Paul G, Marco, Maria, Miles, Timothy J, Read, Kevin D, Gilbert, Ian H
Format: Article
Language:English
Subjects:
Amination
Animals
Chagas Disease - drug therapy
Chagas Disease - parasitology
Chlorocebus aethiops
Drug Discovery
Female
Humans
Mice
Structure-Activity Relationship
Triazoles - chemistry
Triazoles - pharmacokinetics
Triazoles - pharmacology
Triazoles - therapeutic use
Trypanocidal Agents - chemistry
Trypanocidal Agents - pharmacokinetics
Trypanocidal Agents - pharmacology
Trypanocidal Agents - therapeutic use
Trypanosoma cruzi - drug effects
Vero Cells
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00463