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

Brand, S; Ko, EJ; Viayna, E; Thompson, S; Spinks, D; Thomas, M; Sandberg, L; Francisco, AFORCID logo; Jayawardhana, S; Smith, VC; +26 more...Jansen, C; De Rycker, MORCID logo; Thomas, J; MacLean, L; Osuna-Cabello, M; Riley, J; Scullion, P; Stojanovski, L; Simeons, FR; Epemolu, O; Shishikura, Y; Crouch, SD; Bakshi, TS; Nixon, CJ; Reid, IH; Hill, AP; Underwood, TZ; Hindley, SJ; Robinson, SA; Kelly, JMORCID logo; Fiandor, JM; Wyatt, PG; Marco, M; Miles, TJ; Read, KD; Gilbert, IHORCID logo and (2017) Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. Journal of medicinal chemistry, 60 (17). pp. 7284-7299. ISSN 0022-2623 DOI: 10.1021/acs.jmedchem.7b00463
Copy

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.


picture_as_pdf
Discovery and Optimization_GOLD VoR.pdf
subject
Published Version
error
ACS AuthorChoice License
Available under Creative Commons: Attribution-NonCommercial-No Derivative Works 3.0

View Download

Atom BibTeX OpenURL ContextObject in Span Multiline CSV OpenURL ContextObject Dublin Core Dublin Core MPEG-21 DIDL Data Cite XML EndNote HTML Citation JSON MARC (ASCII) MARC (ISO 2709) METS MODS RDF+N3 RDF+N-Triples RDF+XML RIOXX2 XML Reference Manager Refer Simple Metadata ASCII Citation EP3 XML
Export

Downloads