Antiparasitic activities of novel, orally available fumagillin analogs
Arico-Muendel C, Centrella PA, Contonio BD, Morgan BA, O'Donovan G, Paradise CL, Skinner SR, Sluboski B, Svendsen JL, White KF, Debnath A, Gut J, Wilson N, McKerrow JH, DeRisi JL, Rosenthal PJ, Chiang PK.Bioorg Med Chem Lett. 2009 SepAbstract:
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.