jm7b00463_si_002.csv (0.59 kB)
Discovery and Optimization of 5‑Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi
dataset
posted on 2017-08-27, 00:00 authored by Stephen Brand, Eun Jung Ko, Elisabet Viayna, Stephen Thompson, Daniel Spinks, Michael Thomas, Lars Sandberg, Amanda F. Francisco, Shiromani Jayawardhana, Victoria C. Smith, Chimed Jansen, Manu De Rycker, John Thomas, Lorna MacLean, Maria Osuna-Cabello, Jennifer Riley, Paul Scullion, Laste Stojanovski, Frederick R. C. Simeons, Ola Epemolu, Yoko Shishikura, Sabrinia D. Crouch, Tania S. Bakshi, Christopher J. Nixon, Iain H. Reid, Alan P. Hill, Tim Z. Underwood, Sean J. Hindley, Sharon A. Robinson, John M. Kelly, Jose M. Fiandor, Paul G. Wyatt, Maria Marco, Timothy J. Miles, Kevin D. Read, Ian H. GilbertChagas’
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.
