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.
Ansede
John H
JH
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
Anbazhagan
Mariappan
M
Brun
Reto
R
Easterbrook
Judy D
JD
Hall
James Edwin
JE
Boykin
David W
DW
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