Discovery and Preclinical Development of Antigiardiasis Fumagillol Derivatives.

Giardiasis, caused by the intestinal parasite , is a severe diarrheal disease, endemic in poverty-stricken regions of the world, and also a common infection in developed countries. The available therapeutic options are associated with adverse effects, and resistance to the standard-of-care drugs is spreading. Fumagillin, an antimicrosporidiosis drug, is a therapeutic agent with potential for the treatment of giardiasis. However, it exhibits considerable, albeit reversible, toxicity when used to treat immunocompromised microsporidiosis patients. Fumagillin is also a highly unstable compound. To address these liabilities, we designed and synthesized stable fumagillol derivatives with lower levels of permeation across polarized epithelial Caco-2 cells and better potency against trophozoites than fumagillin. Metronidazole-resistant strains were also susceptible to the new fumagillol derivatives. In addition, these compounds were more potent against the amebiasis-causing parasite than fumagillin. Two compounds exhibited better thermal and acid stability than fumagillin, which should prolong the drug shelf life and reduce compound degradation in the stomach. Studies with a mouse model of giardiasis with the most stable compound, 4-(((((3,4,5,6)-5-methoxy-4-((2,3)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl)oxy)carbonyl)amino)benzoic acid (compound 9), revealed that it had better efficacy (effective dose [ED]) than fumagillin at both the fully curative dose (the 100% ED) of 6.6 mg/kg of body weight and a 50% ED of 0.064 mg/kg. Plasma pharmacokinetics revealed the slow absorption of compound 9 through the gut, consistent with the characterization in Caco-2 cells. An acute-dose study yielded a maximum tolerated dose (MTD) of 1,500 mg/kg, 227-fold higher than the fully curative dose. Thus, along with improved stability, compound 9 also exhibited an excellent therapeutic window.