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

作者：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

来源：Journal of Medicinal Chemistry, 2017, 60(17): 7284-7299.

DOI：10.1021/acs.jmedchem.7b00463

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.

• 出版日期2017-9-14