O-alkoxyamidine prodrugs of furamidine: in vitro transport and microsomal metabolism as indicators of in vivo efficacy in a mouse model of Trypanosoma brucei rhodesiense infection.
Five O-alkoxyamidine analogues of the prodrug 2,5-bis[4-methoxyamidinophenyl]furan were synthesized and evaluated against Trypanosoma brucei rhodesiense in the STIB900 mouse model by oral administration. The observed in vivo activity of these prodrugs demonstrates that compounds with an O-methoxyamidine or O-ethoxyamidine group effectively cured all trypanosome-infected mice, whereas prodrugs with larger side-chains did not completely cure the mice. Permeability across Caco-2 cell monolayers and microsomal metabolism were used to identify the underlying mechanisms of prodrug efficacy.
Division of Drug Delivery and Disposition, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA. JohnAnsede@Qualyst.com
John H
JH
Ansede
Mariappan
M
Anbazhagan
Reto
R
Brun
Judy D
JD
Easterbrook
James Edwin
JE
Hall
David W
DW
Boykin
D000284:Administration, Oral; D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport; D018938:Caco-2 Cells; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D016833:Trypanosoma brucei rhodesiense; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D001550:Benzamidines; D011355:Prodrugs; D014344:Trypanocidal Agents; C033286:furamidine