Antiparasitic activities of novel, orally available fumagillin analogs.
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.
Arico-Muendel
Christopher
C
Praecis Pharmaceuticals, 830 Winter Street, Waltham, MA 02451, USA. christopher.c.arico-muendel@gsk.com
Centrella
Paolo A
PA
Contonio
Brooke D
BD
Morgan
Barry A
BA
O'Donovan
Gary
G
Paradise
Christopher L
CL
Skinner
Steven R
SR
Sluboski
Barbara
B
Svendsen
Jennifer L
JL
White
Kerry F
KF
Debnath
Anjan
A
Gut
Jiri
J
Wilson
Nathan
N
McKerrow
James H
JH
DeRisi
Joseph L
JL
Rosenthal
Philip J
PJ
Chiang
Peter K
PK
D000284:Administration, Oral; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D021261:Parasitic Sensitivity Tests; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases