Antiparasitic activities of novel, orally available fumagillin analogs.

Abstract

Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR forms a basis for further optimization of fumagillin based inhibitors against parasitic targets by inhibition of MetAP2.

• Authors: Christopher Arico-Muendel, Paolo A Centrella, Brooke D Contonio, Barry A Morgan, Gary O'Donovan, Christopher L Paradise, Steven R Skinner, Barbara Sluboski, Jennifer L Svendsen, Kerry F White, Anjan Debnath, Jiri Gut, Nathan Wilson, James H McKerrow, Joseph L DeRisi, Philip J Rosenthal, Peter K Chiang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 17 Pg. 5128-31 (Sep 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19648008 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Cyclohexanes
• Fatty Acids, Unsaturated
• Sesquiterpenes
• fumagillin
• Aminopeptidases
• methionine aminopeptidase 2
• Metalloendopeptidases

Topics

• Administration, Oral
• Aminopeptidases (antagonists & inhibitors, metabolism)
• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cyclohexanes (chemical synthesis, chemistry, pharmacology)
• Fatty Acids, Unsaturated (chemical synthesis, chemistry, pharmacology)
• Metalloendopeptidases (antagonists & inhibitors, metabolism)
• Mice
• Parasitic Sensitivity Tests
• Sesquiterpenes (chemical synthesis, chemistry, pharmacology)