Synthesis and comparison of physicochemical, transport, and antithrombic properties of a cyclic prodrug and the parent RGD peptidomimetic

Cyclic prodrug 1 was derived from RGD peptidomimetic 2 by linking the amino and carboxylic acid groups via an (acyloxy)alkoxy linker. The formation of a cyclic prodrug can transiently alter the physicochemical properties of the RGD peptidomimetic. Cyclic prodrug 1 was synthesized via the key intermediate 8, and the synthesis of this key intermediate was accomplished using two different routes. Cyclic prodrug 1 has a smaller hydrodynamic radius and higher membrane interaction potential than those of the parent RGD peptidomimetic 2. The cell membrane permeation of cyclic prodrug 1 is twice that of the parent peptidomimetic 2. The prodrug-to-drug conversion can be carried out in isolated porcine esterase as well as human plasma. The cyclic prodrug is more stable at pH 4 than pH 7, and is very unstable at pH 10. The cyclic prodrug has antithrombic activity, suggesting that it can be converted to the RGD peptidomimetic in platelet-rich plasma (PRP). [Copyright &y& Elsevier]