Synthesis and evaluation of novel coumarin-based esterase-sensitive cyclic prodrugs of peptidomimetic RGD analogs with improved membrane permeability.
Earlier, we reported the development of a coumarin-based prodrug system that could be used for the preparation of cyclic prodrugs of opioid peptides. These cyclic prodrugs exhibited excellent membrane permeability characteristics. Therefore, it was of interest to determine the effects of this prodrug strategy on the membrane permeabilities of peptidomimetics which also have low membrane permeabilities. For this study, we have chosen two RGD (Arg-Gly-Asp) peptidomimetics, which have the potentials to be developed clinically as orally active antithrombotic agents. However, the clinical development of oral dosage forms of these RGD analogs has been hindered by their low intestinal mucosal permeability. Therefore, we have synthesized the corresponding coumarin-based cyclic prodrugs of these RGD peptidomimetics, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. These cyclic prodrugs were shown to have higher membrane interaction potentials, as estimated by their partitioning between aqueous buffer and an immobilized artificial membrane, than the corresponding RGD analogs suggesting that they should exhibit good membrane permeation characteristics. Subsequently, in a separate study these cyclic prodrugs were shown to be 5 to 6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier, than the corresponding RGD peptidomimetics.
Wang
B
B
Department of Chemistry, North Carolina State University, Raleigh 27695-8204, USA.
Wang
W
W
Camenisch
G P
GP
Elmo
J
J
Zhang
H
H
Borchardt
R T
RT
D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003374:Coumarins / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004355:Drug Stability; D004950:Esterases / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship