title: In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi.
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.
authors.affiliation: Instituto Venezolano de Investigaciones, Centro de Bioquimica y Biofisica, Altos de Pipe, Caracas 1020, Venezuela. jaurbina@ivic.ve
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Concepcion
authors.forename: Aura
authors.initials: A
authors.lastname: Caldera
authors.forename: Gilberto
authors.initials: G
authors.lastname: Payares
authors.forename: Cristina
authors.initials: C
authors.lastname: Sanoja
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otomo
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hiyoshi
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D005260:Female; D007700:Kinetics; D050356:Lipid Metabolism; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
chemical_list: C489151:3-((2-benzyl-6-(3-hydroxy-4-methoxypyrrolidin-1-yl)pyridin-3-yl)ethynyl)quinuclidin-3-ol; C489152:3-((2-benzyl-6-(3-methoxypropyloxy)pyridin-3-yl)ethynyl)quinuclidin-3-ol; D004791:Enzyme Inhibitors; D011725:Pyridines; D011812:Quinuclidines; D014344:Trypanocidal Agents; D013186:Farnesyl-Diphosphate Farnesyltransferase