4 years ago

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

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi
Manu De Rycker, Laste Stojanovski, Lorna MacLean, Amanda F. Francisco, Yoko Shishikura, Kevin D. Read, Paul Scullion, Ola Epemolu, Christopher J. Nixon, Tim Z. Underwood, Jennifer Riley, Maria Osuna-Cabello, Elisabet Viayna, Jose M. Fiandor, Maria Marco, Stephen Brand, Ian H. Gilbert, Timothy J. Miles, Iain H. Reid, John M. Kelly, Tania S. Bakshi, Eun Jung Ko, Michael Thomas, Frederick R. C. Simeons, John Thomas, Lars Sandberg, Daniel Spinks, Stephen Thompson, Alan P. Hill, Paul G. Wyatt, Sharon A. Robinson, Victoria C. Smith, Shiromani Jayawardhana, Chimed Jansen, Sean J. Hindley, Sabrinia D. Crouch
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00463

DOI: 10.1021/acs.jmedchem.7b00463

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