Synthesis of a novel cyclic prodrug of RGD peptidomimetic to improve its cell membrane permeation.
The objective of this work was to synthesize cyclic prodrug 2 derived from the parent RGD peptidomimetic 1 and to evaluate its chemical and enzymatic stabilities and antithrombic activity. Cyclic prodrug 2 was formed to improve the cell membrane permeation of RGD peptidomimetic 1 by transiently masking the unfavorable physicochemical properties of compound 1. Cyclic prodrug 2 was synthesized by linking the amino and carboxylic acid groups of parent 1 via the (acyloxy)alkoxy promoiety. The prodrug-to-drug conversion of cyclic prodrug 2 was evaluated in isolated esterase and human plasma in the absence and presence of the esterase inhibitor paraoxon. The rate of hydrolysis of cyclic prodrug 2 was significantly faster in plasma (t(1/2)=33.5+/-0.6 min) than in PBS (t(1/2)=314+/-11 min). Cyclic prodrug 2 was converted by esterase to the parent compound 1 and this conversion was inhibited by an esterase inhibitor, paraoxon. The IC50 (4 micro M) of cyclic prodrug 2 was higher than the IC50 (1.9 micro M) of parent drug 1. The antithrombic activity of cyclic prodrug 2 depends on the incubation time in platelet-rich plasma; the activity increases with incubation time, suggesting that the prodrug-to-drug conversion is time-dependent and mediated by esterase. Cyclic prodrug 2 was more stable under acidic and neutral conditions than under basic conditions, suggesting that handling and formulation of this prodrug should be undertaken under acidic conditions.
Song
Xiaoping
X
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.
Xu
Christine R
CR
He
Henry T
HT
Siahaan
Teruna J
TJ
D000818:Animals; D002463:Cell Membrane Permeability; D004355:Drug Stability; D004950:Esterases / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013552:Swine
D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011355:Prodrugs; C047981:arginyl-glycyl-aspartic acid; D004950:Esterases; D010261:Paraoxon