Dipeptidyl peptidase IV (DPPIV/CD26)-based prodrugs of hydroxy-containing drugs.
We previously described a novel prodrug approach in which a di- or tetrapeptide moiety is linked to a wide variety of amine-containing drugs through an amide bond, which is specifically cleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity. Herein we report the application of this prodrug approach to a variety of hydroxy-containing drugs (primary, secondary, tertiary, or aromatic hydroxy groups). We designed and studied tripartite prodrugs containing a dipeptide moiety (cleavable by DPPIV/CD26) and a valine as a hetero-bifunctional connector to link the dipeptide to the hydroxy group of the drug through a metabolically labile ester bond. The hydroxy-containing prodrugs showed various susceptibilities to hydrolysis by DPPIV/CD26 and serum, depending on the nature of the compound. Prodrugs of compounds containing a primary hydroxy group (as in didanosine) or a hydroxy moiety on an aromatic entity (as in acetaminophen) were most efficiently converted. In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs.
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain.
Alberto
A
Diez-Torrubia
Silvia
S
Cabrera
Anne-Marie
AM
Lambeir
Jan
J
Balzarini
María-José
MJ
Camarasa
Sonsoles
S
Velázquez
D000082:Acetaminophen / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D002166:Camptothecin / Q000737:chemistry; D002417:Cattle; D016049:Didanosine / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D011433:Propranolol / Q000737:chemistry; D012995:Solubility; D014633:Valine / Q000737:chemistry
D000588:Amines; D004151:Dipeptides; D011355:Prodrugs; D000082:Acetaminophen; D011433:Propranolol; D018819:Dipeptidyl Peptidase 4; D014633:Valine; D016049:Didanosine; D002166:Camptothecin