ArticleAntimicrobial agents and chemotherapy2004
In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi.
Article in Antimicrobial agents and chemotherapy, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 89 citations in OpenAlex.
- TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Advances in preclinical approaches to Chagas disease drug discovery.Expert opinion on drug discovery · 2019Review
- Capsular specific IgM enhances complement-mediated phagocytosis and killing of Cryptococcus neoformans by methamphetamine-treated J774.16 macrophage-like cells.International immunopharmacology · 2017Article
- Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii.ChemMedChem · 2016Article
- Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis.Antimicrobial agents and chemotherapy · 2015Article
- SQ109, a new drug lead for Chagas disease.Antimicrobial agents and chemotherapy · 2015Article
- Squalene synthase as a target for Chagas disease therapeutics.PLoS pathogens · 2014Article
- Impact of methamphetamine on infection and immunity.Frontiers in neuroscience · 2014Review
- Methamphetamine enhances Cryptococcus neoformans pulmonary infection and dissemination to the brain.mBio · 2013Article
- Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease.International journal for parasitology. Drugs and drug resistance · 2012Article
- Head-to-head prenyl tranferases: anti-infective drug targets.Journal of medicinal chemistry · 2012Article
- Clinical aspects of Chagas disease and implications for novel therapies.Drug development research · 2011Article
- Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis.Annals of clinical microbiology and antimicrobials · 2011Article
- Mechanism of action and inhibition of dehydrosqualene synthase.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with Trypanosoma cruzi.Antimicrobial agents and chemotherapy · 2010Article
- Drug targets in Leishmania.Journal of parasitic diseases : official organ of the Indian Society for Parasitology · 2010Article
- Synthetic Medicinal Chemistry in Chagas' Disease: Compounds at The Final Stage of "Hit-To-Lead" Phase.Pharmaceuticals (Basel, Switzerland) · 2010Review
- Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.Interdisciplinary perspectives on infectious diseases · 2009Article
- In vitro activities of ER-119884 and E5700, two potent squalene synthase inhibitors, against Leishmania amazonensis: antiproliferative, biochemical, and ultrastructural effects.Antimicrobial agents and chemotherapy · 2008Article
- Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth.Chemistry & biology · 2007Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K(i) values in the low nanomolar to subnanomolar range in the absence or presence of 20 microM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.
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