A coumarin-based prodrug strategy to improve the oral absorption of RGD peptidomimetics

Wei Wang, Gian Camenisch, David C. Sane, Huijuan Zhang, Erin Hugger, Guy L. Wheeler, Ronald T. Borchardt, Binghe Wang

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


In recent years, major progress has been made in the design and synthesis of fibrinogen antagonists, which are peptidomimetic Arg-Gly-Asp (RGD) analogs. These RGD analogs are very promising antiplatelet agents. However, the clinical development of orally active RGD analogs has been hindered by the low oral bioavailability of many such RGD analogs. Aimed at enhancing their oral bioavailability, we have synthesized several coumarin- based cyclic prodrugs of RGD analogs, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. As expected, these cyclic prodrugs have higher membrane interaction potentials as estimated by determining their partitioning between aqueous buffer and an immobilized artificial membrane than the corresponding RGD analogs. Consequently, these cyclic prodrugs are 5-6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier. Preliminary studies using dog also indicate the promising potential of using this coumarin-based prodrug strategy to improve the oral bioavailability of such RGD analogs. (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)245-251
Number of pages7
JournalJournal of Controlled Release
Issue number1-2
StatePublished - Mar 1 2000
Externally publishedYes


  • Coumarin
  • Drug delivery
  • Fibrinogen
  • Membrane permeability
  • Platelet

ASJC Scopus subject areas

  • Pharmaceutical Science


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