Application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to different amine-containing drugs.
Here we explore the applicability of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to a variety of amine-containing drugs. Efficient procedures have been developed for the synthesis of dipeptide and tetrapeptide amide prodrugs including N-acylation protocols of the exocyclic amino function of cytidine and adenosine nucleosides. Our studies demonstrated that XaaPro dipeptides linked to a free amino group present on an aromatic ring or on a sugar entity are prodrugs that efficiently release the parent drug upon conversion by purified DPPIV/CD26 as well as soluble DPPIV/CD26 in bovine and human serum. Vildagliptin, a specific inhibitor of DPPIV/CD26, was able to completely block the hydrolysis of the prodrugs in the presence of purified CD26 but also in human and bovine serum. When the amino group is present on a pyrimidine or purine ring, the dipeptide derivatives are chemically unstable, whereas the tetrapeptide derivatives (i.e., ValProValPro or ValAlaValPro) were much more stable in solution and efficiently converted to the parent drug by the action of DPPIV/CD26. This DPPIV/CD26-directed prodrug technology can be useful to increase solubility of the parent drug molecules and/or to allow better formulation properties.
Diez-Torrubia
Alberto
A
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
García-Aparicio
Carlos
C
Cabrera
Silvia
S
De Meester
Ingrid
I
Balzarini
Jan
J
Camarasa
María-José
MJ
Velázquez
Sonsoles
S
D000218:Adamantane / Q000031:analogs & derivatives; D000588:Amines / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D009570:Nitriles; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000378:metabolism; D011759:Pyrrolidines; D012995:Solubility; D013329:Structure-Activity Relationship; D000077597:Vildagliptin
D000588:Amines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D009842:Oligopeptides; D011355:Prodrugs; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane