Cryptosporidium parvum is an important mammalian pathogen and class B bioterrorismagent. This waterborne protozoan parasite relies exclusively on the salvage of adenosine to obtain guanine nucleotides in a pathway that includes inosine 5'-monophosphate dehydrogenase (IMPDH). Structural differences between human IMPDH (hIMPDH) and C. parvum IMPDH (CpIMPDH) suggested a strategy for the design of CpIMPDH-selective inhibitors. Here, we report the SAR of a urea-based inhibitor series. All inhibitors show greater than 103-fold selectivity for CpIMPDH with nanomolar to sub-nanomolar IC50 values.  Several compounds display excellent potency and selectivity in a Toxoplasma gondii model of C. parvum infection. The best compounds have anti-cryptosporidial activity in a tissue culture model of infection, are stable in mouse liver microsomes, mouse plasma and acidic conditions.  These compounds are promising candidates for treating cryptosporidiasis.

Highly potent and selective inhibitors for <i>Cryptosporidium parvum</i> inosine 5'-monophosphate dehydrogenase: SAR and anticryptosporidial activity

240th National Meeting (2010)

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Highly potent and selective inhibitors for Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase: SAR and anticryptosporidial activity