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

In recent years, major progress has been made in the design and synthesis o f fibrinogen antagonists, which are peptidomimetic Arg-Gly-Asp (RGD) analog s. These RGD analogs are very promising antiplatelet agents. However, the c linical development of orally active RGD analogs has been hindered by the l ow oral bioavailability of many such RGD analogs. Aimed at enhancing their oral bioavailability, we have synthesized several coumarin-based cyclic pro drugs of RGD analogs, which have the two most polar functional groups, a ca rboxyl and an amino group, masked as an ester and an amide, respectively. A s expected, these cyclic prodrugs have higher membrane interaction potentia ls as estimated by determining their partitioning between aqueous buffer an d an immobilized artificial membrane than the corresponding RGD analogs. Co nsequently, these cyclic prodrugs are 5-6-fold more able to permeate monola yers of Caco-2 cells, an in vitro cell culture model of the intestinal muco se barrier. Preliminary studies using dog also indicate the promising poten tial of using this coumarin-based prodrug strategy to improve the oral bioa vailability of such RGD analogs. (C) 2000 Elsevier Science B.V. All rights reserved.